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 .
The information disclosure statement, filed on 9/8/26, is acknowledged. However, the Yiwen reference has been lined through since it is already of record on the 892 mailed 3/4/26.
Applicant's amendment and remarks, filed 7/6//26, are acknowledged.
Claims 1-9 are pending and are under examination.
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 1-4, 6-8 is/are rejected under 35 U.S.C. 103 as being unpatentable over KR20170113961 (as evidenced by English, machine translation), in view of Schultz, 1999 (of record), and Lee-Chang, 2016 (of record).
The ‘961 publication teaches a method of making a B cell vaccine comprising introducing an expression vector encoding 4-1BBL into B cells such that the B cells express 4-1BB (i.e. collecting 4-1BBL+ B cells, see pages 3 and 10 of the translation). The ‘961 publication teaches culturing said B cells after transfection with anti-CD40 agonist antibody for 2 days (i.e. at least 12 hours, See pages 10-11 of the translation, in particular). The ‘961 publication further teaches sensitizing the B cells to a foreign antigen, such as a tumor antigen (i.e. contact with tumor derived antigens, see pages 5-6, in particular). The ‘961 publication teaches the use of the B cells as a vaccine for treating cancer, and teaches that the B cells can be from autologous tissues (i.e. from a subject with cancer, See page 2, in particular). The ‘961 publication teaches examples of cancer can include breast cancer and melanoma (see page 6 of the translation, in particular).
The reference differs from the claimed invention in that it does not explicitly teach adding IFN-gamma to the B cells.
Schultze teaches that adding IFN-gamma to CD40L stimulated B cells increases IL-12 production by B cells and enhances T cell stimulation (See Fig. 3-4 and page 7, in particular). Schultze teach using 20 ng/ml of IFN-gamma for up to 96 hours in culture (See page 3, in particular).
Lee-Chang teaches that 4-1BB+ B cells are important for inducing anti-tumor immune responses, and that IFN-gamma can activate 4-1BB+ B cells to provide further cos-stimulation and TNF production for inducing T cell responses (See abstract, and pages 3394-3396 and Fig. 7, 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 make include IFN-gamma, as taught by Schulze and Lee-Chang, in the CD40 agonist B cell culture of the ‘961 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 Schultz teaches that IFN-gamma increases IL-12 production and T cell stimulatory capacity of CD40 activate B cells, and Lee-Chang also teaches that IFN-gamma can active 4-1BB+ B cells to further increase stimulation and TNF production for inducing T cell responses. Regarding claim 8, the ‘961 publication teaches a 2 day culture with CD40L agonist before antigen loading, and it would be obvious to add IFN-gamma during the CD40L step because Schultze teaches that it can increase T cell stimulation capacity when used in combination with CD40L for up to 96 hours. Regarding claim 7, a concentration of 20 ng/ml would comprise at least 10 U/ml of IFN-gamma activity, or alternatively, it would be obvious to optimize the amount of IFN-gamma. “[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).
Applicant’s arguments filed 7/6/26 have been fully considered, but they are not persuasive.
Applicant argues that the ‘961 publication teaches recombinantly producing 4-1BBL+ B cells, since naturally occurring cells are difficult to use, and therefore teaches away from the claimed invention that requires collecting 4-1BBL+ B cells.
The present claims broadly recite a step of “collecting 4-1BB+ B cells”. The ‘961 publication teaches collecting 4-1BB+ B cells by a process of isolation and genetic modification, which is within the scope of the claimed method. The present claims are directed to a method “comprising” the recited steps, which is an open term that does not exclude unrecited steps or elements. For example, the ‘961 publication teaches recombinantly expressing 4-1BB in B cells and collecting the resulting 4-1BB+ B cells by centrifugation, which is within the scope of the claimed method.
Applicant further argues that it would not have been obvious to add IFN-gamma to the CD40 stimulated B cells of the ‘961 publication based on the teachings of Schultz because the B cells in each reference are different cells and not interchangeable. Applicant argues that in the ‘961 publication the B cells are murine B cells isolated from the spleen using CD43, and Shultz teaches CD40 activated non-germinal center B cells, and the effects of different cytokines and stimulatory molecules on different types of B cells would be unpredictable.
The teachings of the ‘961 publication are not limited to using CD43 B cells from the mouse spleen. The ‘961 publication teaches that “the B cells used for transformation can be obtained through a known B cell separation technique and not particularly limited” (see page 3, in particular). Thus, one could use the B cells of Schulz, separated from human peripheral blood, as the source of B cells in the method of the ‘961 publication with a reasonable expectation of success. Furthermore, both cited references teach that the B cells are stimulated via CD40 and Shultz teaches that IFN-gamma increases IL-12 production by CD40 stimulated B cells. See also Lee-Chang which teaches that IFN-gamma can activate 4-1BB+ B cells to provide further co-stimulation and TNF production for inducing T cell responses. The references provide motivation and reasonable expectation of success in including IFN-gamma along with CD40 mediated signals in B cell cultures to achieve the advantages taught by Shultz and Lee-Chang.
Claim 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over KR20170113961 (as evidenced by English, machine translation), Schultz, 1999, Lee-Chang, 2016, as applied to claim 1 above, and further in view of WO2019086711 (of record).
The teachings of the ‘961 publication, Schultz, and Lee-Chang. are discussed above.
The references do not teach culturing with BAFF.
WO2019086711 teaches APC, such as B cells that are engineered to express 4-1BB, wherein the B cells are activated by incubation with CD40L (see paragraphs 20-26, 195-196, in particular). WO2019086711 teaches that the APCs are contacted with a tumor antigens (See paragraph 60). WO2019086711 teaches the importance of IL-12 production by the B cells in inducing T ell responses (See, for example, paragraphs 264-265). WO2019086711 also teaches that the B cells can further be cultured with other compounds including cytokines and activators of BAFF/BAFFR signaling pathway, (see paragraphs 196-197, 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 further include activators of BAFF/BAFFR, such as BAFF, as taught by WO2019086711, in the B cell cultures made obvious by the ‘961 publication, Schultz, and Lee-Chang. The ordinary artisan at the time the invention was made would have been motivated to do so with a reasonable expectation of success, because WO2019086711 teaches that BAFF can be included to activate B cells in 4-1BB+, CD40 stimulated B cell cultures used for loading with tumor antigens.
Applicant’s arguments filed 7/6/26 have been fully considered, but they are not persuasive.
Applicant argues that the claims are not obvious for the reasons set forth above.
The claims stand rejected for the same reasons set forth above.
Claim 1-4, 6-9 is/are rejected under 35 U.S.C. 103 as being unpatentable Lapointe, 2003, in view of Lee-Chang, 2014, Lee-Chang 2016 (all of record), and Rousset, 1991.
Lapointe teach a method of preparing B cells comprising collecting B cells from peripheral blood, expanding the B cells by incubating with a CD40 agonist and IL-4, and subsequently contacting the B cells with tumor lysate antigens (see page 2837, in particular). Lapointe teach that the B cells are autologous B cells from a melanoma patient (See page 2837, in particular). Lapointe teach using CD40L as the CD40 agonist (i.e. CD154, see page 2837, in particular). Lapointe teach culturing with CD40 agonist for 3-8 days before contacting with the tumor cell lysate antigen (see page 2837, in particular). As taught by Lee-Chang, 2014, peripheral blood B cells comprise a subset that are 4-1BBL+ (See page 1453, in particular). Thus, the collected B cells of Lapointe would comprise 4-1BBL+ cells (i.e. it would be a latent property of the collected B cells), and would be within the scope of step (a) of the present claims, which recites collecting 4-1BBL+ B cells.
The reference differs from the claimed invention in that it does not explicitly teach adding IFN-gamma to the B cells.
Rousset teach that including IFN-gamma, along with IL-4 and CD40 stimulation, increases B cell expansion (see page 706, in particular). Rousset teach culturing for 3-7 days (i.e. at least 10 hours). Rousset teach using 500 U/ml IFN-gamma (see page 706, 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 further add IFN-gamma, as taught by Rousset, in the CD40 agonist B cell cultures of Lapointe. The ordinary artisan at the time the invention was made would have been motivated to do so with a reasonable expectation of success, because Rousset teaches that IFN-gamma enhances B cell expansion.
Although the presence of 4-1BB+ B cells would be a latent property of the B cells of Lapointe for the reasons set forth above, it would also be obvious to include 4-1BB+ B cells in the method of Lapointe based on the teachings of Lee-Chang 2014 and 2016. In particular, Lee-Chang, 2014 teaches that 4-1BB+ B cells are found in patients with cancer, and that they can induce anti-tumor T cells. Lee-Chang 2016 also teaches that 4-1BB+ B cells accumulate in cancer patients, and that 4-1BB+ B cells can take up tumor antigens and induce tumor antigen specific T cell responses (See page 3395, in particular). Lee-Chang 2016 also teaches that said 4-1BB+ B cells are activated by CD40L and IFN-gamma to induce anti-tumor T cell responses (see Fig. 7, in particular). Therefore, it would be obvious when collecting B cells from cancer patients, as taught by Lapointe, that they should include 4-1BB+ B cells, since they induce anti-tumor T cells. Furthermore, the ordinary artisan would have a reasonable expectation of success in including them in the B cell cultures made obvious by Lapointe and Rousset, since Lee-Chang, 2016 teaches that they are activated by CD40L and IFN-gamma to induce anti-tumor T cell responses.
Applicant’s arguments filed 7/6/26 have been fully considered, but they are not persuasive.
Applicant argues that Lapointe does not disclose the collection of 4-1BBL cells, since there is insufficient evidence that 4-1BB+ B cells are included in the B cells collected by LaPointe.
LaPointe teach purifying B cells from peripheral blood, i.e. collecting the B cells, wherein the B cells are CD19+. As evidenced by Lee-Chang, 2014, human CD19+ B cells from peripheral blood contain from 6-13% 4-1BB+ B cells (depending on the age of the subject, see Fig. 1). See also Fig 1 of the instant specification wherein CD19+ B cells from peripheral blood contain a 4-1BB+ subset. Thus, the B cells collecting in Lapointe would inherently comprise a subset (6-13%) that are 4-1BB+. The present claims broadly recite a step of “collecting 4-1BBL+ B cells”. The claims do not require any particular level of purity, nor do they recite any limiting steps for how they are collected. The broadest reasonable interpretation of the claimed collection step would encompass the method of Lapointe, wherein CD19+ B cells are collected from peripheral blood, wherein a fraction of said collected cells would inherently be 4-1BBL+.
Alternatively, as noted above, it would also be obvious to include 4-1BB+ B cells in the method of Lapointe based on the teachings of Lee-Chang 2014 and 2016. In particular, Lee-Chang, 2014 teaches that 4-1BB+ B cells are found in patients with cancer, and that they can induce anti-tumor T cells. Lee-Chang 2016 also teaches that 4-1BB+ B cells accumulate in cancer patients, and that 4-1BB+ B cells can take up tumor antigens and induce tumor antigen specific T cell responses (See page 3395, in particular). Lee-Chang 2016 also teaches that said 4-1BB+ B cells are activated by CD40L and IFN-gamma to induce anti-tumor T cell responses (see Fig. 7, in particular). Therefore, it would be obvious when collecting B cells from cancer patients, as taught by Lapointe, that they should include 4-1BB+ B cells, since they induce anti-tumor T cells. Furthermore, the ordinary artisan would have a reasonable expectation of success in including them in the B cell cultures made obvious by Lapointe and Rousset, since Lee-Chang, 2016 teaches that they are activated by CD40L and IFN-gamma to induce anti-tumor T cell responses.
Applicant further argues that there would no reasonable expectation of success in replacing the B cells of Lapointe with the 4-1BBL+ B cells of Chang, because Chang and Lapointe teach that the B cells have conflicting functions. Applicant notes that Lapointe teach that resting B cells can be tolerogenic and may require activation signals. Lee-Chang teaches that aging alters the distribution of B cells and that they can have tumor supporting activity or tumor inhibiting activity.
As an initial matter, it is noted that the B cells of Lapointe would inherently comprise 4-1BBL+ B cells and would be within the scope of the claims for the reason set forth above. However, it would also be obvious to collect 4-1BBL+ B cells, since Lee-Chang 2014 teaches that 4-1BB+ B cells are found in patients with cancer, and that they can induce anti-tumor T cells. Lee-Chang 2016 also teaches that 4-1BB+ B cells accumulate in cancer patients, and that 4-1BB+ B cells can take up tumor antigens and induce tumor antigen specific T cell responses (See page 3395, in particular). Lee-Chang 2016 also teaches that said 4-1BB+ B cells are activated by CD40L and IFN-gamma to induce anti-tumor T cell responses (see Fig. 7, in particular). Therefore, it would be obvious when collecting B cells from cancer patients, as taught by Lapointe, that they should include 4-1BB+ B cells, since they induce anti-tumor T cells. Furthermore, the ordinary artisan would have a reasonable expectation of success in including them in the B cell cultures made obvious by Lapointe and Rousset, since Lee-Chang, 2016 teaches that they are activated by CD40L and IFN-gamma to induce anti-tumor T cell responses.
Applicant further argues that Rousset teaches that IFN-gamma had no effect on enhancing B cell proliferation, and only IL-4 was found to be effective.
Rousset teach that a combination of IL-4, CD40L- and IFN-gamma further stimulated cell multiplication and resulted in 80-90 fold expansion of CD19+ B cells (see Fig. 1B, page 706-707). Thus, the ordinary artisan would be motivated to further include IFN-gamma, in the cultures of Lapointe which include IL-4 and CD40L, to achieve the 80-90 fold increase expansion taught by Rousset with a reasonable expectation of success.
Claim 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lapointe, 2003, in view of Lee-Chang, 2014, Lee-Chang 2016, and Rousset, 1991, as applied to claim 1 above, and further in view of Yiwen.
The teachings of the Lapointe, Lee-Chang, and Rousset, are discussed above.
The references do not teach culturing with BAFF.
Yiwen teaches that including BAFF in CD40L activated B cell cultures enhances expansion efficiency and antigen presenting capacity of B cells.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to include BAFF, as taught by Yiwen, in the B cell cultures activated with CD40L and IFN-gamma as made obvious by Lapointe, Lee-Chang , and Rousset. The ordinary artisan at the time the invention was made would have been motivated to do so with a reasonable expectation of success, because Yiwen teaches that including BAFF in CD40L activated B cell cultures enhances expansion efficiency and antigen presenting capacity of B cells
Applicant’s arguments filed 7/6/26 have been fully considered, but they are not persuasive.
Applicant argues that the claims are not obvious for the reasons set forth above.
The claims stand rejected for the same reasons set forth above.
No claim is allowed.
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
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