DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant's amendment and remarks, filed 12/16/25, are acknowledged.
Claims 1, 3-4, 11-12 have been amended.
Claims 1, 3-4, 6-7, 9-12 are pending and are under examination.
Claim 11 is objected to for the following informalities: The claims recites “The of claim 1” and administering the TIL population “to a treat” cancer. Correction to recite “The method of claim 1” and “to treat cancer” is required.
In view of Applicant’s claim amendments, only the following rejections remain.
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.
Claim(s) 1, 3-4, 6-7, 9-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2012/0244133 (of record), in view of US 20050106717, Harao, 2015, Ullenhag, 2012, and Hu, 2013 (of record).
The ‘133 publication teaches a method of rapidly producing an expanded TIL population comprising plating and culturing a tumor tissue sample of a subject into a gas permeable culture vessel, and culturing in a complete medium comprising IL-2 (see page 2 and 6 of the ‘133 publication, in particular). The ‘133 publication further teaches removing half the medium and replacing with fresh medium and IL-2 every 3 days thereafter, i.e. exchanging the media in the reservoir at least two times per week, see page 2, in particular. The ‘133 publication teaches plating a tumor tissue sample comprising tumor fragments directly without performing digestion (see page 2 and 6, in particular). The ‘133 publication teaches that the tumor tissue sample can be from a biopsy (see page 2, in particular). The ‘133 publication further teaches that the TILs are cultured for about 28 days (i.e. 5 weeks or less), and harvesting the expanded TIL population and administering the TIL population to treat cancer in the subject (see pages 3-4, in particular). The ‘133 publication teaches that the tumor tissue fragment may be any suitable size and that the gas permeable container can have a range of surface areas and volume capacities (see page 2, in particular). For example, the ‘133 publication teaches tumor fragments having a size of about 1-8 mm3 or larger. See also page 6 which discloses a single tumor fragment of approximately 1 to 8 mm3 in size can be plated in a single well of a 24 well plate. Thus, the ordinary artisan can readily envision using a single reservoir, such as a single plate for culture. Regarding the TIL yield, the ‘033 publication teaches that culture of TIL from tumor fragments in gas permeable vessel increased TIL yield (see pages 7-8 and Table 2, in particular). The ‘033 publication also teaches the use of the tumor fragments increases yield compared to dissociated, digested tumors. For example, the ‘033 publication teaches an example wherein 8.13 x 108 TIL were obtained using tumor fragments, as compared to 4.94 x 107 TIL using dissociated and digested tumor, i.e. at least 6 times greater yield (see examples and Table 2, in particular). The ‘033 publication teaches that the gas permeable culture vessel can be any suitable container, and specifically teaches that it may be as described in U.S. Patent Application 2005/0106717. The ‘017 publication teaches various types of gas permeable culture devices, including those configured in a multiple well format of a variety of capacities and dimensions which allow larger volumes of medium compared to traditional plates (see page 11 and Fig. 8-9, in particular).
The reference differs from the claimed invention in that it does not explicitly teach using a core biopsy.
Ullenhag teach a method of rapidly producing an expanded TIL population comprising obtaining a core needle biopsy and suspending a piece of the biopsy in 2 ml complete medium and IL-2 and replacing the media every 2-3 days thereafter to expand the cells (See page 726, in particular). Ullenhag also teach that current protocols for TIL generation rely on open surgery for access to tumor tissue, and that obtaining the tissue via core needle biopsy is advantageous since it is robust, safe, and inexpensive approach to obtaining tumor tissue for TIL generation (See page 725, in particular).
Harao also teaches expanding TIL from core biopsy samples and that 4-6 mm2 tumor fragments were cultured in 24 well plates with IL-2 to expand the T cells. Harao also teaches that anti-4-1BB can be included in the TIL cultures and that doing so greatly increases the percentage, yield and cytolytic activity of CD8+ TIL.
Hu teaches that the size of a core needle biopsies relate to the size of the needle used and can range from a tissue volume of 0.5-10 mm3, or up to 150mm3 (see Fig. 1, in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use a tissue sample from a core needle biopsy, as taught by Ullenhag, Harao, and Hu, as the type of biopsy tissue sample in the method of expanding TIL taught by the ‘133 publication. The ordinary artisan at the time the invention was made would have been motivated to do so with a reasonable expectation of success, because Ullenhag teach that core needle biopsies are advantageous for TIL expansion, since they are robust, safe, and inexpensive approach that avoids open surgery.
Regarding the limitation that the method results in a TIL yield at least 6 times greater than the yield, it is noted that the references teach various parameters that can be optimized to increase TIL yield. For example, the ‘033 publication teaches the use of gas permeable vessels as opposed to traditional plates and the use of fragments as opposed to dissociated/digested samples increased cell yield. Furthermore, Harao also teaches that anti-4-1BB greatly increases cell yield. Therefore, it would be routine to optimize the method to produce greater than 6 times yield.
It would be obvious to optimize the plating with an appropriate size core biopsy in a single gas permeable plate by placing one core biopsy sample directly into well of a multi well plate, for example, based on the teachings of the cited references. For example, the ‘133 publication teaches tumor fragments having a size of about 1-8 mm3 or larger and discloses a single tumor fragment of approximately 1 to 8 mm3 in size can be plated in a single well of plate. Furthermore, as taught by Hu, core needle biopsies can have a range of sizes including 0.5-10mm3. Therefore, it would be well within the purview of the ordinary artisan to plate a core biopsies into each well of a mutli well gas permeable plate. Additionally, the ordinary artisan would also be motivated to include anti-4-1BB in the cultures as taught by Harao, since the reference teaches that it greatly increases the percentage, yield, and cytolytic activity of CD8+ TIL.
Applicant’s arguments filed 12/16/25 have been fully considered, but they are not persuasive.
Applicant argues that as shown in Fig. 5 and 6, using a single core biopsy sample provides unexpected results as compared to traditional resection based methods. In contrast, Applicant argues that Ullenhag teaches that both core biopsy samples and surgically resected tissue provide comparable yields.
To establish unexpected results, Applicant must compare the claimed invention with the closest prior art. Applicant cites Figure 6 which shows higher yield after a shorter culture time (17/18 days) using a gas permeable flask as compared to standard culture vessels.
However, this is an expected beneficial result. For example, the ‘133 publication teaches that the gas permeable culture vessel facilitates gas exchange and facilitates respiration, growth, viability and feeding of the cells (see pages 2-3, in particular). See also the examples, wherein the ‘133 publication teaches that a head to head comparison of culturing in gas permeable and non-gas permeable vessels shows that TIL yields from the gas permeable vessels were consistently higher (See page 8, in particular). The ‘133 publication also teaches that gas permeable culture vessel, as compared to traditional, non-gas permeable culture vessel produces a greater number of TIL in a shorter period of time, i.e. in a reduce culture time period, see page 7, in particular.
Regarding Fig. 5, the conditions used for the comparison are not clear, i.e. what size fragments, how many, how were they were treated (dissociated enzymatically, etc.). It appears that the results of Fig. 5 are a comparison of core biopsies with traditionally digested tumor fragments. However, achieving higher yields using a non-dissociated tumor fragment, such as a core biopsy, as compared to dissociated tumor fragments, would also be an expected result based on the teachings of the ‘133 publication for the reasons set forth above. The figure legend for Fig. 5 indicates that it shows that a single core biopsy in a single well resulted in better yield than multiple fragments in a single well. Regarding the number of fragments, the ‘133 publication also teaches comparing the number of tumor fragments, wherein the quantities of TIL obtained per tumor fragment decreased as the number of pieces added was increased and that adding too many fragments to a culture vessel of a particular size can decrease overall yield (see page 8, in particular). Therefore, obtaining different yields by varying the amount of tumor tissue or fragment per culture vessel is also not unexpected “Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof.” In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967)
Applicant has also argued that Ullenhag teaches that both core biopsy samples and surgically resected tissue provide comparable yields, making the results in the instant specification unexpected. To the extent Applicant would consider Ullenhag to be the closest prior art, it is not clear how the results in Fig. 5 would be unexpected compared to Ullenhag, since the reference teaches using one core biopsy sample per well. The difference from Ullenhag would be the use of a gas permeable plate, however, achieving a better yield than Ullenhag by using a gas-permeable culture vessel would also be expected based on the cited prior art. Ullenhag do not explicitly disclose the culture conditions for the surgically resected tissue (i.e. is it digested, amount used to per well, etc.). The fact that Ullenhag may show similar yield as compared to a different culture method than used as the basis of comparison by Applicant is not sufficient to establish unexpended results.
See MPEP 716.02. “[A]ppellants have the burden of explaining the data in any declaration they proffer as evidence of non-obviousness.” Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd. Pat. App. & Inter. 1992). The evidence relied upon should establish “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.” Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). It is noted that the error bars in Fig. 5 appear to overlap and Applicant has not cited any evidence that this is a statistically significant result. An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). Objective evidence of nonobviousness must also be commensurate in scope with the claims which the evidence is offered to support. For example, it is not clear if the culture conditions, media, and times are the same as the claimed method, and the results are also not commensurate in scope with the instant claims.
The present claims do recite a limitation that the method yields at least 6 times greater yield that resection based methods comprising surgical resection of a tumor followed by production of multiple fragments, digestion, and culturing of the multiple fragments. Regarding yield, Ullenhag teaches that surgical resection allows for larger volumes of tissue, which is directly correlated to the number of TIL. Thus, Ullenhag suggests similar yields despite having a much larger tissue volume using the resected tissue as compared to core biopsy (see page 731, surgery allows for larger tissue volumes which is directly correlated to the numbers of TILs). In other words, Ullenhag would imply that the per tissue volume yield using core biopsy is actually higher than using resected tissue (same yield, but from much smaller volume of tissue using core biopsy as compared to resected tissue).
It is also noted that the claimed yield limitation does not require a particular type of yield (i.e. the claim could encompass TIL yield per tissue volume or per culture well) and also does not require comparison to yield resulting from, for example a core biopsy and resected fragments cultured under identical conditions. The yield comparison is broadly claimed as compared to yield obtained via resection based methods “comprising” surgical resection of a tumor followed by production of multiple fragments, digestion, and culturing of the multiple fragments. For example, the instant specification on page 10 discloses that the claimed method improves TIL yield at least 6 times greater that the yield obtained by traditional methods, and discloses on page 3 discloses that the traditional methodology is i.e. surgical resection followed by fragment production, digest, and culture of multiple fragments in a single well of a regular 24 well plate. In other words, the 6 times greater yield limitation of the present claims encompasses a comparison to production of multiple fragments, digestion, and culturing in a regular 24 well plate. As noted above, the ‘133 publication specifically teaches increased yield using gas permeable culture vessel. Furthermore, the ‘133 publication also teaches comparing the number of tumor fragments, wherein the quantities of TIL yield obtained per tumor fragment decreased as the number of pieces added was increased and that adding too many fragments to a culture vessel of a particular size can decrease overall yield (see page 8, in particular). Therefore, one could also expect to obtain a greater per fragment TIL yield using a single core biopsy fragment as compared to the per fragment TIL yield from a culture containing multiple fragments, which is a comparison within the scope of the claims. Furthermore, the ‘131 publication also teaches that TIL yield in cultures without tumor fragment digestions, as compared to with digestions increased yield. Therefore, it would be obvious that yield could be increase at least 6 times using a single core biopsy fragment without digestions, as compared to using multiple fragments, digested fragments and culture of digested fragments in regular 24 well plates, which meets the limitation of the instant claims. See also instant claim 7, which recites including 41BB, and would encompass obtaining 6 fold greater yield using a core biopsy culture with 4-1BB as compared to resection based methods comprising surgical resection of a tumor followed by production of multiple fragments, digestion and culture of the multiple fragments without 4-1BB, would also be expected and obvious based on the teachings of the cited references given that including 4-1BB increases TIL yield.
Applicant further argues that Ullenhag teaches that other publications have shown that surgical samples are more likely to contain TILs, and that a disadvantage of core biopsies is the disability to created autologous tumor cell lines and having less tissue for histopathological analysis. Applicant argues that the reference teaches away from the use of core biopsies.
Ullenhag specifically teaches reactivity of TILs was comparable between tissues obtained by surgery and core biopsy, and also teach the advantage of using a core needle biopsy sample, which include being considerably less expensive to perform, requiring only local anesthesia, taking only a few minutes to complete, leaving no scar tissue, and allows most patients to rapidly resume normal activity. Ullenhag also teaches that it allows sampling of metastases that are inaccessible to surgery (See page 732, in particular). Ullenhag concludes that core needle biopsy of melanoma lesions is a reliable method for generation of relevant numbers of TILs for therapy, and is highly pertinent in cases where surgery is not applicable and will facilitate the accessibility and dissemination of current protocols for TIL generation to multiple centers. Thus, Ullenhag do not teach away from the use of core biopsies, as argued by Applicant.
Even to the extent that Ullenhag may teach advantages and disadvantages to the selection of a core biopsy versus surgically resected biopsy, this does not constitute a teaching away. “The prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
Applicant further argues that although Harao mentions core biopsies, the authors only mentions TILs from tumor fragments. Applicant cites another publication by the same author, Harao, 2017, wherein no mention of core biopsies was made. Applicant argues that Hu only deals with core biopsies for diagnose of lymphoma and does not provide information as the tissue size for satisfactorily expanding TILs.
References may be relied upon for all that they suggest to the ordinary artisan and Harao specifically mentions using (the fact that other studies used a different source of tissue is not relevant, see above, the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
Furthermore, 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).
The ’133 publication provides teaching of the size of tissue samples necessary for providing TILs. Hu is relied upon for teaching what sizes of tissue sample can be expected using a core biopsy. As set forth above, both Ullenhag and Harao teach the suitability of core biopsy samples for expanding TILs.
Claim(s) 1, 3-4, 6-7, 9-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015/157636, in view of US 2012/0244133 (of record), US 20050106717, and Hu, 2013 (of record).
WO 2015/157636 teaches a method of rapidly producing an expanded TIL population comprising obtaining a tumor tissue sample by cutting fragments from a core biopsy of a subject, plating the tissue sample comprising the core biopsy fragment in a multi well plate; and culturing TILs from the tumor tissue sample in a medium comprising IL-2 and anti-41BB antibody (see pages 42-44 and Figure 12, in particular). WO 2015/157636 teaches that the tumor sample is obtained and plated without enzymatic digestion or mechanical dissociation, i.e. it is directly plated without disaggregated (See Fig. 12, pages 42-44 and Table 1, in particular). WO 2015/157636 teaches a 4 week culture timeframe (see page 43, in particular). WO 2015/157636 teaches that the culturing process involves feeding with fresh media and IL-2 (see page 34, in particular). WO 2015/157636 further teaches that the TIL can be harvested and used for administration to a subject to treat cancer (See page 9 and 22, in particular). It would be obvious that one could put the each tissue sample into a single well of a multi well plate, for example (See Fig. 11).
The reference differs from the claimed invention in that it does not explicitly teach a gas permeable tissue culture multi well plate, or exchanging the media at least two times per week.
The ‘133 publication teaches a method of rapidly producing an expanded TIL population comprising directly culturing a tumor tissue sample of a subject into a gas permeable culture vessel, and culturing in a complete medium comprising IL-2, (see page 2 and 6 of the ‘133 publication, in particular). The ‘133 publication further teaches removing half the medium and replacing with fresh medium and IL-2 every 3 days thereafter, i.e. exchanging the media in the reservoir at least two times per week, see page 2, in particular. The ‘133 publication teaches that the tumor tissue fragment may be any suitable size and that the gas permeable container can have a range of surface areas and volume capacities (see page 2, in particular). For example, the ‘133 publication teaches tumor fragments having a size of about 1-8 mm3 or larger (see page 2, in particular). See also page 6 which discloses a single tumor fragment of approximately 1 to 8 mm3 in size can be plated in a single well of a plate. The ‘033 publication teaches that culture of TIL from tumor fragments in gas permeable vessel increased TIL yield (see pages 7-8 and Table 2, in particular). The ‘133 publication taches that the gas permeable culture vessel facilitates gas exchange and facilitates respiration, growth, viability and feeding of the cells (see pages 2-3, in particular). The ‘033 publication also teaches the use of the tumor fragments increases yield compared to digested tumors. For example, the ‘033 publication teaches an example wherein 8.13 x 108 TIL were obtained using tumor fragments, as compared to 4.94 x 107 TIL using dissociated and digested tumor, i.e. at least 6 times greater yield (see examples and Table 2, in particular). The ‘033 publication teaches that the gas permeable vessel can be any suitable container, and specifically teaches that it may be as described in U.S. Patent Application 2005/0106717. The ‘017 publication teaches various types of gas permeable culture devices, including those configured in a multiple well format of a variety of capacities and dimensions which allow larger volumes of medium compared to traditional plates (see page 11 and Fig. 8-9, in particular).
Hu teaches that the size of a core needle biopsies relate to the size of the needle used and can range from a tissue volume of 0.5-10 mm3, or up to 150mm3 (see Fig. 1, in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use a gas permeable reservoirs, such as a gas permeable multiple well plate, as taught by the ‘133 publication and the ‘017 publication, as the tissue culture plate in the method of WO 2015/157636. The ordinary artisan at the time the invention was made would have been motivated to do so with a reasonable expectation of success, because the ‘133 publication teaches that the gas permeable culture vessels increase TIL yield, facilitates gas exchange and facilitates respiration, growth, viability and feeding of the cells. Furthermore, it would be obvious and well within the purview of the ordinary artisan to culture the cells with a media exchange using complete medium at least 2 times a week as specifically taught by the ‘133 publication.
Regarding the limitation that the method results in a TIL yield at least 6 times greater than the yield, it is noted that the references teach various parameters that can be optimized to increase TIL yield. For example, the ‘033 publication teaches the use of gas permeable vessels as opposed to traditional plates and the use of fragments as opposed to digested samples increased cell yield. WO 2015/157636 also teaches that anti-4-1BB increases cell yield
It would also be obvious to optimize the plating with an appropriate size core biopsy in a single gas permeable plate or well based on the teachings of the cited references. For example, the ‘133 publication teaches tumor fragments having a size of about 1-8 mm3 or larger and discloses a single tumor fragment of approximately 1 to 8 mm3 in size can be plated in a single well of plate. Furthermore, as taught by Hu, core needle biopsies can have a range of sizes including 0.5-10mm3. Therefore, it would be well within the purview of the ordinary artisan to plate one core biopsies into a well of a multi well gas permeable plate.
Applicant’s arguments filed 12/16/25 have been fully considered, but they are not persuasive.
Applicant argues that WO 2015157636 teaches that the cell yield was not different in surgical and core biopsy specimens, and the present invention provides unexpected results between the two. Applicant further argues that the instant specification describes the teachings of WO 2015157636 and characterizes the references as showing that prior attempts to use biopsy specimens have not been successful. Applicant asserts that the reference teaches that TIL generation requires surgical tumor removal, dividing into fragments and processing the fragments into a digest.
References may be relied upon for all that they suggest to the ordinary artisan, and WO 2015157636 explicitly teaches using core biopsies or surgically resected tissue, without enzymatic digestion to produce TILs (See, Fig. 12 in particular). In Fig. 12, the enzymatic digestion is performed for deriving tumor cells and FACs analysis, not for TIL culture. Applicant concedes that the reference teaches similar cell yield using surgical and core biopsy, and it is unclear how Applicant can assert that this means the reference characterizes core biopsies as failing to generate TIL. In contrast to Applicant’s assertion, WO 2015157636 explicitly teaches the suitability of core biopsy samples for producing TIL.
Furthermore, 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).
Regarding Applicant’s arguments of unexpected results, this is not persuasive for the reasons set forth above.
It is additionally noted that Applicant has not specifically indicated how the results in Fig. 5 and 6 represent a comparison with the closest prior art of WO 2015157636.
For example, in Fig. 12, WO 2015157636 teaches similar yield per fragment by culturing one surgical specimen fragment per well as compared to one core biopsy fragment per well (see Fig. 12, page 43, in particular). In contrast, Fig. 5 of the instant specification compares 1 core biopsy per well to multiple enzymatically digested fragments per well, which is not a valid comparison to the closest prior art. Achieving higher yield by using a gas permeable culture vessel in the method of WO 2015157636 would be expected based on the teachings of the ’133 publication for the reasons set forth above.
Regarding the claimed limitation of 6 times greater yield, Fig. 12 of WO 2015157636 does not teach away from greater yield within the scope of the instant claims. In other words, the claims do not require a greater per fragment yield using core biopsy and a resected tumor fragment cultured under identical conditions. For example, one could expect greater yield using the method of WO 2015157636 with gas permeable culture as compared to enzymatically dissected multiple fragments cultured in standard culture vessels based on the teachings of the other cited prior art references for the reasons set forth above.
Applicant is essentially arguing that it would be unexpected based on WO 2015157636, to achieve a greater per fragment yield when culturing a same sized resected tumor fragment and a core biopsy fragment under identical conditions. However, Applicant has not in any way demonstrated such an unexpected result. Rather, the asserted unexpected results cite by Applicant all appear to be a comparison of a core biopsy culture with tumor samples processed using a different methodology (i.e. enzymatically) or to samples cultured using different culture conditions (i.e. gas permeable vs. standard). Nor do the claims require 6 times greater per fragment yield using identical culture conditions for the reasons set forth above.
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, 3-4, 6-7, 9-12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5, 9-13, 16 and 20-24 of copending Application No. 17/279,327 in view of US 2012/0244133, US 20050106717, Hu, 2013 and Harao, 2015. The ’327 application claims a method of expanding a TIL population for use in adoptive cell therapy comprising culturing TIL directly from a bulk, non-purified tumor digest in a culture medium comprising IL-2, wherein the tumor digest comprises one or more core biopsy tissue samples digested with one or more enzymes, wherein the one or more core biopsies are digested without disaggregating. This would meet the limitation of a tissue sample from one or more core biopsy, wherein the biopsies are directly plated without disaggregating the specimen. It would also meet the limitations of claim 12, since the claim is directed to a method comprising the recited steps which does not exclude unrecited steps or elements (i.e. a sample comprising the core biopsy that is obtained, digested, and plated in the method of the ‘327 application would be within the scope of steps a) and b) of claim 12). Furthermore, as the ‘327 application explicitly claims that the biopsy is not disaggregated, this would also meet the limitation being “intact”. The ‘327 application claims using complete medium culturing for 5 weeks or less, further harvesting the expanded TILs, and administering the TILs to s subject to treat cancer.
The ‘327 application does not explicitly claim culturing in a gas permeable tissue culture well plate or exchanging the media at least 2 times a week. However, it would be obvious do so based on the teachings of the ‘133 publication and the ‘717 publication, since the references teach advantages such as facilitating gas exchange respiration, growth, viability and feeding TIL cells. The ‘133 publication also teaches replacing the IL-2 containing medium at least twice a week . Furthermore, it would also be obvious to play a single biopsy, to further culture with 41BB, and to arrive at 6 fold cell yield, based on the teachings of the ‘133 publication Hu, and Harao for the reasons set forth above.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3-4, 6-7, 9-12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-16, 19-24 of copending Application No. 18/555,584, OR over claims 1-7, 10-15, 24-28 of copending Application No. 18/842,179, in view of US 2012/0244133 , US 20050106717, Hu, 2013 and Harao, 2015. The applications both claim a method of expanding a TIL population for use in adoptive cell therapy comprising culturing TIL directly from a bulk, non-purified tumor digest in a culture medium comprising IL-2, wherein tumor digest comprises one or more core biopsy tissue samples digested with one or more enzymes, wherein the one or more core biopsies are digested without disaggregating. This would meet the limitation of a tissue sample from one or more core biopsy, wherein the biopsies are directly plated without disaggregating the specimen. It would also meet the limitations of claim 12, since the claims is directed to a method comprising the recites steps which does not exclude unrecited steps or elements (i.e. sample comprising the core biopsy that is obtained, digested, and plated in the method of the applications would be within the scope of steps a) and b) of claim 12). Furthermore, as the applications explicitly claim that the biopsy is not disaggregated, this would also meet the limitation being “intact”. The applications claim using complete medium culturing for 5 weeks or less, further harvesting the expanded TILs, and administering the TILs to s subject to treat cancer.
The copending applications do not explicitly claim culturing in a gas permeable tissue culture well plate or exchanging the media at least 2 times a week. However, it would be obvious do so based on the teachings of the ‘133 publication and the ‘717 publication, since the references teach advantages such as facilitating gas exchange respiration, growth, viability and feeding TIL cells. The ‘133 publication also teaches replacing the IL-2 containing medium at least twice a week . Furthermore, it would also be obvious to play a single biopsy, to further culture with 41BB, and to arrive at 6 fold cell yield, based on the teachings of the ‘133 publication Hu, and Harao for the reasons set forth above.
This is a provisional nonstatutory double patenting rejection.
Applicant’s statement that the rejections be held in abeyance until allowance is acknowledged.
The following is a new ground of rejection necessitated by Applicant’s claim amendment.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 12 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 12 recites the limitation "the expanded TIL" in part d), line 11 of the claim. There is insufficient antecedent basis for this limitation in the claim.
No claim is 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 extension fee 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 date of this final action.
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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644