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 .
Status of the Claims
Claims 1 and 3-7 are pending.
Claims 1 and 3-5 are newly amended.
Claims 6 and 7 are newly added.
Claims 1 and 3-7 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Withdrawn Objections & Rejections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 Any objections or rejections not specifically reiterated are hereby withdrawn.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 the claims under 35 USC 103 are maintained but modified in order to address the claims as amended.
Claim Rejections - 35 USC § 103 - maintained
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 and 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Hoffmeister et al. (WO2020078498, published 04/23/2020, on IDS 01/02/2024, previously cited) in view of Diaz-Montero et al. (Cancer Immunology Immunotherapy, previously cited) and Chacon et al. (PLOS ONE, 2013, previously cited).
In regards to claims 1 and 7, Hoffmeister teaches methods for extracting autologous tumor infiltrating lymphocytes (TILs, autologous T lymphocytes) from tumor tissues (thus, ex vivo) (Abstract; Description, p1, 10). Hoffmeister teaches that these cells are useful for therapeutic applications and transplantation purposes (Description, p5-6) and are hypertoxic to tumor cells (Description, p10). Since the TILs are autologous from tumor tissues and hypertoxic to those tissues, a person of ordinary skill in the art would have recognized that the method is suitable to use as a patient-specific therapeutic for combating tumors.
In a first stage, Hoffmeister teaches that the tissues are cut into small pieces (thus, comminuted), introduced, evenly distributed, and cultured in a closed meander perfusion bioreactor vessel to obtain TILs (claim 1; Description, p2; Example 1, p 7-9; Example 2, p9-10).
In regards to the limitation of “a defined number of cells”, it is noted that the claims do not require culture a specific number of cells, and therefore, this claim has been interpreted as broadly allowing for any amount of cells. As the tissues as taught by Hoffmeister comprise TILs, they contain a defined number of cells.
Hoffmeister teaches that cells grow in culture medium located in the perfusion meander bioreactor (Abstract; claim 1) and are simultaneously activated and expanded (multiplied) (Example 1, p9 Example 2, p9).
Hoffmeister teaches that medium flows through a channel of the bioreactor with an over flow with a Froud number of not greater than (thus, less than) 0.005 and a bottom flow with a Froud number close to (i.e., about) 0 (claim 1).
Hoffmeister teaches that the medium has directed laminar flow over sedimented cells, which prevents cell stress, which causes rapid growth (expansion) of cells and separation from tissues (Claim 1; Culture medium, p8; Example 1, p8; Example 2, p10).
Hoffmeister teaches that following this step, cells are harvested, centrifuged, and resuspended in a freezing medium in vials (Description, p6; Example 1, p9). Continuing, Hoffmeister teaches that cells are aliquoted and cryopreserved (Description, p6; Example 1, p9).
In a second stage Hoffmeister teaches that vials are thawed, the freezing medium is washed out, and resuspended in a suitable medium (Description, p6; Example 1, p9).
Hoffmeister teaches that following this, cells are transferred to a second (larger) operationally installed meander perfusion bioreactor (Description, p6; Example 1, p9). Hoffmeister teaches that the second bioreactor has a settlement ratio of 3:1 to 20:1 (Description, p6), which overlaps with the claimed range of “a larger settlement area in the ratio of 5 to 1” as in claim 1.
Hoffmeister teaches that media in the bioreactors is perfused with oxygen and is regulated (thus, “in a directed manner”) (Description, p3, 8).
In regards to the medium, Hoffmeister teaches that the medium is supplemented with AB human serum, cytokines, and antibodies (Description, p6 and 9), that oxygen conditions can be hyperoxemic (hyperoxic) (Description, p6), and automatically controlled (Description, p8).
Hoffmeister teaches that the cells grow from the bottom surface (thus, at the bottom of the sedimentation) of the channel of the meander perfusion bioreactor (claim 1).
In regards to whether the cells are largely dormant after sedimentation, and form a cell layer in which they touch and light movements occur, Applicant should note that this appears to be a property or natural consequence of culturing TILs in a perfusion meander bioreactor as in claim 1, not an active method step. Since Hoffmeister teaches culturing TILs in the same bioreactor, they would be expected to also be largely dormant after sedimentation, and form a cell layer in which they touch and light movements occur absent evidence to the contrary.
In regards to the amounts of cells, Hoffmeister teaches that more than 500 million (5 x 108) TILs can be regularly expanded in the bioreactor (Example 1, p9). Hoffmeister also teaches that the bottom of the bioreactor (sedimentation layer) can be between 30 and 500 cm2 (claim 1). Taken together a bioreactor with a 500 cm2 bottom would produce cells at a concentration of 1 x 106 TIL/cm2 which overlaps with the claimed ranges.
While, as above, Hoffmeister teaches that the medium is supplemented with cytokines and antibodies, Hoffmeister is silent as to the specific types of cytokines or antibodies.
In regards to the cytokine being IL-12, a person of ordinary skill in the art would have been motivated to stimulate TILS with the cytokine being IL-12 because Diaz-Montero teaches that IL-12 primed CD8+ T cell populations show superior anti-tumor activity and that culturing naïve CD8+ T cells with IL-12 rescues subsets from in reduced cell death and increased accumulation (Abstract, p564). Furthermore, because Diaz-Montero teaches that T cells can be primed in the presence of the cytokine IL-12 (Fig. 4) and because as above, Hoffmeister teaches that the medium is supplemented with cytokines, it could have been done with predictable results and a reasonable expectation of success.
In regards to the antibody being 4-1BB, a person of ordinary skill in the art would have been motivated to stimulate TILs with the antibody being 4-1BB because Chacon teaches that 4-1BB antibody increases yield of CD8+ T cells, increases their anti-tumor CTL activity, produces T cell populations capable of improved effector function and survival, and suggests that this improves TIL persistence and anti-tumor activity in vivo after adoptive transfer into patients (Abstract, p1). Furthermore, because Chacon teaches that T cells can be contacted with 4-1BB antibody (Results, p4-5; Fig. 1, p5), and because as above, Hoffmeister teaches that the medium is supplemented with antibodies, it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 6, as above, Hoffmeister teaches an over flow with a Froud number of not greater than (thus, less than) 0.005 (claim 1), which overlaps with a Froud number of 0.002.
Therefore, the combined teachings of Hoffmeister, Diaz-Montero, and Chacon renders the invention unpatentable as claimed.
Claims 3 is rejected under 35 U.S.C. 103 as being unpatentable over Hoffmeister et al. (WO2020078498, published 04/23/2020, on IDS 01/02/2024, previously cited) in view of Diaz-Montero et al. (Cancer Immunology Immunotherapy, previously cited) and Chacon et al. (PLOS ONE, 2013, previously cited), as applied to claims 1 and 2 above, and further in view of MP Biomedicals (Cat. No. 092780248, 2019, previously cited), Li et al. (Cytotherapy, 2019), Lotze et al. (US20200121719A1, 2020, previously cited), and Becherucci et al. (Biopreservation and Biobanking, 2020, previously cited).
In regards to claim 3, as above, Hoffmeister teaches that cryopreserved vials are thawed, the freezing medium is washed out, and resuspended in a suitable medium (Description, p6; Example 1, p9).
While Hoffmeister is silent on whether washing out was performed by centrifugation, a person of ordinary skill in the art would have been motivated to wash out cryopreservation medium by centrifugation because as taught by MP Biomedicals centrifugation is a known technique for washing and recovering cryopreserved cells (column 2). Furthermore, because it is well-established in the art that thawed cells are centrifuged to remove cryopreservation medium, because MP Biomedicals teaches that centrifugation is a suitable technique to remove cryopreservation medium, and because in other steps Hoffmeister teaches that TILs can be centrifuged for separation (Description, p9), it could have been done with predictable results and a reasonable expectation of success.
As above, Hoffmeister teaches that following this, cells are transferred to a second (larger) operationally installed meander perfusion bioreactor (Description, p6; Example 1, p9).
Hoffmeister also teaches that TILs expand over 12 to 20 days and then are washed in a NaCl solution(Description, p6; Example 1, p9).
In regards to centrifugation, a person of ordinary skill in the art would have been motivated to centrifuge cells in order to remove them from contaminating media. Furthermore, because in other steps, Hoffmeister teaches that TILs can be centrifuged to separate them and because it is well-established in the art that cells are centrifuged for separation from media, it could have been done with predictable results and a reasonable expectation of success.
Hoffmeister is silent as to the concentration of NaCl, and does not explicitly teach that the solution comprises 2% albumin or 10% DMSO.
Furthermore, while Hoffmeister teaches that cryopreserved cells are stored over nitrogen (Description, p9), Hoffmeister also does not explicitly teach a step of further resuspending cells in defined portions in 100 mL cryobags after a conventional cooling process and stored over nitrogen (thus, a second cryopreservation step)
However, a person of ordinary skill in the art would have been motivated to subsequently cryopreserve expanded TILs (which would require a “conventional” cooling process) in order to save them for further use. Additionally, because Hoffmeister teaches that TILs may be cryopreserved, it could have been done with predictable results and a reasonable expectation of success.
In regards to the solution (cryopreservation medium), a person of ordinary skill in the art would have been motivated to use a solution comprising DMSO and albumin, because Li teaches that T cells and other immune cells are commonly cryopreserved in media comprising DMSO and albumin and that this is suitable for clinical application (Abstract, p1; Cryopreserved T lymphocytes in clinical trials, p45). Furthermore, because Li teaches that it is well-known in the art that T cells are cryopreserved with DMSO (Abstract, p1; Cryopreserved T lymphocytes in clinical trials, p45; Table 1, p20) it could have been done with predictable results and a reasonable expectation of success.
In regards to the concentrations, Li teaches that T cells are cultured at 10% DMSO which overlaps with the range as in claim 3.
In regards to albumin, Li teaches known formulations with 5% human serum albumin (Table 1, p20), which is close to the claimed 2% (see MPEP 2155.05, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).
Additionally, a person of ordinary skill in the art could have arrived at a concentration of 2% by routine optimization and the disclosure does not point to a criticality in this percentage (see MPEP 2144.05(II)(A), 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)). In the instant case, because Li teaches that it is known in the art that T cells are cryopreserved in media supplemented with albumin at a range of concentrations (from 5% to 50%)(Table 1, p20), a person of ordinary skill in the art could have arrived at a concentration of 2% by routine optimization with predictable results and a reasonable expectation of success.
In regards to the concentration of NaCl, Li teaches that known formulation of cryopreservation media comprise 0.45% NaCl, which is also close to the claimed 0.9% (Table 20, p1; indeed, PlasmaLyte-A comprises 0.45% NaCl, 5% HSA, and 7.5% DMSO, which is close to the claimed percentages of 0.9%, 2%, and 10% respectively).
Furthermore, a person of ordinary skill in the art could have arrived at a concentration of 0.9% NaCl by routine optimization, the disclosure does not point to a criticality in this concentration, and because Li teaches that it is known that lymphocytes can be cultured in a range of NaCl, from 0.45% NaCl (table 1, p20) to 0.9% (Table 2, p22), a person of ordinary skill in the art could have arrived at the concentration of 0.9% NaCl by routine optimization with predictable results and a reasonable expectation of success.
A person of ordinary skill in the art would have been motivated to store cryopreserved cells over nitrogen because Li teaches that it is known in the art that T cells can be stored in liquid nitrogen for therapeutic use (Table 1, p20).
In regards to a cryobag (a cryopreservation bag), a person of ordinary skill in the art would have been motivated to use a cryobag because Becherucci teaches that blood cells may be stored with a controlled rate of freezing and in nitrogen in cryobags that store volumes between 80 and 150 mL, which overlaps with the range of 100 mL, and stored for at least 6 months (Abstract, p454; Table 1, p455). Furthermore, because Becherucci demonstrates that blood cells may effectively be cryopreserved in bags ((Abstract, p454; Fig. 2, p457) it could have been done with predictable results and a reasonable expectation of success.
Finally, as above, Hoffmeister teaches that frozen vials are thawed (Description, p6; Example 1, p9). A person of ordinary skill in the art would have recognized that this would require retrieving those vials. Furthermore, as above, Hoffmeister teaches that these cells are useful for therapeutic applications and transplantation purposes (Description, p5-6). While Hoffmeister is silent on whether the TILs are specifically dosed to the patient, a person of ordinary skill in the art would have been motivated to dose cells to patients in order to not elicit a pathological immune response and to ensure an adequate amount of therapeutic cells. Furthermore, because Lotze teaches that populations of TILs can be dosed to patients (claim 20), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Hoffmeister, Diaz-Montero, Chacon, MP Biomedicals, Li, Becherucci, and Lotze renders the invention unpatentable as claimed.
Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Hoffmeister et al. (WO2020078498, published 04/23/2020, on IDS 01/02/2024, previously cited) in view of Diaz-Montero et al. (Cancer Immunology Immunotherapy, previously cited) and Chacon et al. (PLOS ONE, 2013), as applied to claims 1 and 2 above, and further in view of Lotze et al. (US20200121719A1, 2020, previously cited).
In regards to claims 4 and 5, since as above, Hoffmeister teaches that these cells are useful for therapeutic applications and transplantation purposes (Description, p5-6), a person of ordinary skill in the art would have recognized that the TIL composition of Hoffmeister is a pharmaceutical composition.
Additionally, as above, since is well-known in the art that as TILs come from a patient’s own tumor cells, a person of ordinary skill in the art would have recognized that pharmaceutical composition is used for the treatment of tumors.
Additionally, as taught by Lotze, it was known in the art before the effective filing date that TILs could be formulated as pharmaceutical compositions for the treatment of cancers including ovarian cancer (claim 139). A person of ordinary skill in the art would have been motivated to utilize the TIL composition of Hoffmeister as a pharmaceutical composition for treating cancers, such as ovarian cancer, to alleviate disease in these patients. Furthermore, because Hoffmeister teaches that the TIL composition can be sued for therapeutic applications and because Lotze teaches that TIL pharmaceutical compositions can be specifically used for treating cancers such as ovarian cancer, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Hoffmeister, Diaz-Montero, Chacon, and Lotze renders the invention unpatentable as claimed.
Response to Arguments
Applicant argues that Hoffmeister does not teach measuring density in the sedimented layer (Remarks, p9).
Applicant’s arguments filed 06/12/2026 have been fully considered but are not found persuasive.
As discussed above, teaches that the cells grow from the bottom surface (thus, at the bottom of the sedimentation) of the channel of the meander perfusion bioreactor (claim 1).
Indeed, in claim 1, Hoffmeister explicitly describes these cells as “sedimented cells” (“Concentration of nutrients, as well as no flow-causing flow in the overflowing medium of the sedimented cells ensures”).
Therefore, a person of ordinary skill in the art would have recognized that the cells are in fact sedimented.
Applicant argues that in regards to the amounts of cells of 500 million (5 x 108) TILs is taken from Example 1, while claim 1 separate mentions that the bottom of the bioreactor be between 30 and 500 cm2 (Remarks, p8).
Specifically, Applicant argues that the Office’s reasoning provides no correspondence or connection between the amount of more than 500 million cells mentioned in Example 1 and the surface area of the bioreactor separately set forth in claim 1 (Remarks, p8).
Applicant argues that the Office has not provided a total yield and reactor area that occur in the same embodiment (Remarks, p8).
Applicant argues that claim 1 requires that the density of the cells in the sedimented layer and that this density range is not fairly suggested by dividing the cell amount and surface area from disparate passages of Hoffmeister (Remarks, p8).
Applicant’s arguments filed 06/12/2026 have been fully considered but are not found persuasive.
In regards to Applicant’s arguments against combining the teachings from the claims with the teachings from the Examples in the disclosure of Hoffmeister, according to MPEP 2123, patents are relevant as prior art for all they teach, and specifically, a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989).
In the instant case, the claims provide a broad framework, while the examples provide working embodiments of that framework.
Furthermore, according to MPEP 2164.02(III), for a claimed genus, representative examples together with a statement applicable to the genus as a whole will ordinarily be sufficient if one skilled in the art (in view of level of skill, state of the art and the information in the specification) would expect the claimed genus could be used in that manner without undue experimentation.
Thus, because Hoffmeister broadly teaches that the bottom of the bioreactor (sedimentation layer) can be between 30 and 500 cm2 (claim 1), and then gives a specific example, that more than 500 million (5 x 108) TILs can be regularly expanded in the bioreactor (Example 1, p9), a person of ordinary skill in the art would have recognized that these were any amount of cells that could be produced the dimensions of bioreactor as disclosed within claim 1.
Furthermore, as above, Hoffmeister teaches that the cells grow from the bottom surface (thus, at the bottom of the sedimentation) of the channel of the meander perfusion bioreactor (claim 1).
Indeed, in claim 1, Hoffmeister explicitly describes these cells as “sedimented cells” (“Concentration of nutrients, as well as no flow-causing flow in the overflowing medium of the sedimented cells ensures”).
Therefore, a person of ordinary skill in the art would have recognized that the cells are in fact sedimented.
Hoffmeister teaches that more than 500 million (5 x 108) TILs can be regularly expanded in the bioreactor (Example 1, p9). Hoffmeister also teaches that the bottom of the bioreactor (sedimentation layer) can be between 30 and 500 cm2 (claim 1). Taken together a bioreactor with a 500 cm2 bottom would produce cells at a concentration of 1 x 106 TIL/cm2 which overlaps with the claimed ranges.
Applicant argues that this would require hindsight to reconstruct these numbers (Remarks, p8).
Applicant’s arguments filed 06/12/2026 have been fully considered but are not found persuasive.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Indeed, as above, this is specifically an amount lies within the scope of Hoffmeister.
As above, because Hoffmeister broadly teaches that the bottom of the bioreactor (sedimentation layer) can be between 30 and 500 cm2 (claim 1), and then gives a specific example, that more than 500 million (5 x 108) TILs can be regularly expanded in the bioreactor (Example 1, p9), a person of ordinary skill in the art would have recognized that these were any amount of cells that could be produced the dimensions of bioreactor as disclosed within claim 1.
Applicant argues that in regards to the limitations requiring the cells to be “largely dormant” and “form a cell layer in which they touch and light movement occur” are not inherent properties (Remarks, p9). Applicant also argues that inherency must necessarily flow from the teachings of the prior art citing In re Rijckaert (Remarks, p9-10).
In particular, Applicant argues that Hoffmeister does not teach the claimed concentration of cells, and therefore, argues that the Office has not established that all the forgoing limitations are taught or suggested by Hoffmeister (Remarks, p10).
Applicant’s arguments filed 06/12/2026 have been fully considered but are not found persuasive.
In regards to the concentration of cells in the sedimentation layer, as discussed above, Hoffmeister teaches that the cells grow from the bottom surface (thus, at the bottom of the sedimentation) of the channel of the meander perfusion bioreactor (claim 1).
Indeed, in claim 1, Hoffmeister explicitly describes these cells as “sedimented cells” (“Concentration of nutrients, as well as no flow-causing flow in the overflowing medium of the sedimented cells ensures”).
Therefore, a person of ordinary skill in the art would have recognized that the cells are in fact sedimented.
Additionally, Hoffmeister teaches that more than 500 million (5 x 108) TILs can be regularly expanded in the bioreactor (Example 1, p9). Hoffmeister also teaches that the bottom of the bioreactor (sedimentation layer) can be between 30 and 500 cm2 (claim 1). Taken together a bioreactor with a 500 cm2 bottom would produce cells at a concentration of 1 x 106 TIL/cm2 which overlaps with the claimed ranges.
Therefore, the concentration of cells within the sedimented layer, is an embodiment of the method as taught by Hoffmeister.
In regards to whether the cells are largely dormant after sedimentation, and form a cell layer in which they touch and light movements occur, as above, this is property or natural consequence of culturing TILs in a perfusion meander bioreactor as in claim 1, not an active method step.
Therefore, the claim specifically suggest that the claimed method steps alone are sufficient to result in cells with the properties.
As discussed above, Hoffmeister teaches these same method steps. As a result, they would have these same properties absent evidence to the contrary.
In regards to Diaz-Montero and Chacon, applicant argues that setting forth reasons why a skilled artisan might consider IL-12 and anti-4-1BB individually is not tantamount to justifying why a skilled artisan would have selected both modifications simultaneously (Remarks, p11). Citing MPEP 2143.01, which states that “The mere fact that references can be can be combined does not render the resultant combination unless the results would have been predictable to one of ordinary skill in the art”, Applicant argues that the cited art does not suggest that the combined use of IL-12 and antagonistic anti-4-1BB antibody would provide additive or complementary effects (Remarks, p11).
Applicant’s arguments filed 06/12/2026 have been fully considered but are not found persuasive.
It is noted that the MPEP does not require a justification as to why a person of ordinary skill in the art would have selected both modifications simultaneously or why the combination would have provided additive or complementary effects, only that there was a motivation to modify the prior art that that the modification could have been done with predictable results and a reasonable expectation of success (see MPEP 2141).
As discussed above, in regards to the cytokine being IL-12, a person of ordinary skill in the art would have been motivated to stimulate TILS with the cytokine being IL-12 because Diaz-Montero teaches that IL-12 primed CD8+ T cell populations show superior anti-tumor activity and that culturing naïve CD8+ T cells with IL-12 rescues subsets from in reduced cell death and increased accumulation (Abstract, p564). Furthermore, because Diaz-Montero teaches that T cells can be primed in the presence of the cytokine IL-12 (Fig. 4) and because as above, Hoffmeister teaches that the medium is supplemented with cytokines, it could have been done with predictable results and a reasonable expectation of success.
In regards to the antibody being 4-1BB, a person of ordinary skill in the art would have been motivated to stimulate TILs with the antibody being 4-1BB because Chacon teaches that 4-1BB antibody increases yield of CD8+ T cells, increases their anti-tumor CTL activity, produces T cell populations capable of improved effector function and survival, and suggests that this improves TIL persistence and anti-tumor activity in vivo after adoptive transfer into patients (Abstract, p1). Furthermore, because Chacon teaches that T cells can be contacted with 4-1BB antibody (Results, p4-5; Fig. 1, p5), and because as above, Hoffmeister teaches that the medium is supplemented with antibodies, it could have been done with predictable results and a reasonable expectation of success.
In regards to Applicant’s arguments that IL-12 and 4-1BB are “antagonistic”, this assertion is not supported by the art and Applicant has not provided evidence that they are beyond mere assertion.
Applicant argues that the claims require a hyperoxic or normoxic supply of supplemented medium depending on the increased amount of TIL or other T cells through an automatically controlled supply and that the cited portions of Hoffmeister do not disclose automatic adjustment of oxygen and supplemented medium in response to increasing TIL populations but rather merely regulation of oxygenation in a general sense (Remarks, p11-12).
Applicant’s arguments filed 06/12/2026 have been fully considered but are not found persuasive.
As above, Hoffmeister teaches that media in the bioreactors is perfused with oxygen and is regulated (thus, “in a directed manner”) (Description, p3, 8). As above, Hoffmeister also teaches that that oxygen conditions can be hyperoxemic (hyperoxic) (Description, p6), and automatically controlled (Description, p8). In regards to “depending on the increased amount of TIL or other T cells”, the claim does not require any specific changes to oxygen in regards to any specific amount of cell growth (i.e., the claim does not require a specific increase or decrease in oxygen depending on volume of cell growth). Therefore, the claim broadly allows for any normoxic or hyperoxic oxygen level at any amount of cells. Thus, because Hoffmeister teaches that cells can be automatically controlled to hyperoxic conditions, the teachings of Hoffmeister read on this broad limitation.
Applicant argues that the rejections over 4-7 should be withdrawn or are patentable over the cited prior art (Remarks, p13).
Applicant’s arguments filed 06/12/2026 have been fully considered but are not found persuasive.
Claim 1 is prima facie obvious as discussed above. Furthermore, dependent claims 4-7 are also individually prima facie obvious also as discussed above.
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 JOSEPH (PAUL) MIANO whose telephone number is (571)272-0341. The examiner can normally be reached Mon-Fri from 8:30am to 5:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James (Doug) Schultz can be reached at (571) 272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
Prosecution Insights