DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Amendments
In the reply filed on 12/16/2025, Applicant has amended claims 1 and 8-11, newly canceled claims 2, 4-5, 12-13, 16-20 and 24-27, and added new claims 30-34.
Claim Status
Claims 1, 3, 8-11 and 30-34 are pending and are considered on the merits. Claims 1, 8 and 9 are independent claims.
Withdrawn Claim Objections
The prior objection to claims 1 and 10-11 because of not spelling out abbreviations or typographic errors, is withdrawn in light of Applicant’s amendment.
New Claim Objections
Claims 10-11 are objected to because of the following informalities:
Claims 10-11 both newly recite the term “Intereukin-1β” in line 4, which contains a typographic error. It is recommended to change to “Interleukin-1β”.
Appropriate correction is required.
Withdrawn Claim Rejections - 35 USC § 112
The prior rejection of claims 10-11 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendment to the claims.
New Claim Rejections - 35 USC § 112(a)
NEW MATTER
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3, 8-11 and 30-34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The new limitation of the BHK cell or CHO cell (or the mammalian cell) “only expresses a single heterologous protein” in instant claims (e.g., independent claims 1, 8 and 9) represents new matter. Regarding the new limitation, a review of the specification by the Examiner only found support of “rabbit CD40L-expressing mammalian cells” (e.g., [0010]), but did NOT find any specific basis for the recited limitation of the mammalian cells “only expresses a single heterologous protein”.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 1, 3 and 8-11 under 35 U.S.C. 103 set forth in the prior Office action mailed on 10/08/2025, is withdrawn in light of Applicant’s amendment to the independent claims 1, 8 and 9 to recite new limitations “a single antibody secreting rabbit IgG+ B cell” and “the BHK cell of CHO cell (or the mammalian cell) only expresses a single heterologous protein”, that are not discussed in the prior rejection.
New Claim Rejections - 35 USC § 103
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 3 are rejected under 35 U.S.C. 103 as being unpatentable over Kitamura et al., (WO2011052545A1, published 05/05/2011. Cited in IDS 04/13/2023. The corresponding US patent publication US2012/0214192 is referred to hereinafter as “Kitamura” in consistent with Applicant’s remarks) in view of Tiller (N Biotechnol. 2011; 28(5): 453-457) and Blair et al., (Immunity. 2010; 32: 129-140. Prior art of record).
With respect to independent claim 1, Kitamura teaches a method for producing an antigen-specific B cell population which contains IgG-positive B cells that are specific to a particular antigen (see e.g., abstract), thus teaches a method for producing an antibody (i.e., from IgG-positive B cells).
In regard to the step of co-cultivating a rabbit antibody secreting IgG+ B cell with a rabbit CD40L expressing cell in the presence of IL-2 and IL-21, Kitamura teaches IgG-positive B cells are cultured together with the particular antigen in the presence of IL-21, while providing the IgG-positive B cells with stimulation through CD40 (see e.g., abstract). Kitamura teaches the B cell population used in the present invention may be a cell population derived from an organism with an established immune system, such as … Mammalian rodents such as … rabbits ([0037]), thus suggests a rabbit B cell. Kitamura teaches examples of the origin of CD40L, … include … small mammal rodents… it may be derived from the same species as the cell population to be presented ([0048]), thus suggests a rabbit CD40L to culture with a rabbit B cell. Kitamura teaches the CD40L expressing cells include fibroblasts, epithelial cells, fetal kidney cells, and follicular dendritic cells ([0052]) and uses irradiated 3T3 cells (mouse embryonic fibroblasts) as an example for coculturing with B cells ([0098]). Kitamura teaches other cytokines may be used together with IL-21, for example, when IL-2 is used in combination with IL-21, the concentration of IL-2 is preferably 1 ng/ml to 1 μg/ml (e.g., [0076], also see Example 5 in [0120]), thus teaches coculturing B cells in the presence of IL-2 and IL-21.
Accordingly, it would have been obvious for one of ordinary skill in the art before the date of the claimed invention being made to have chosen a rabbit B cell and a rabbit CD40L in the method of co-cultivating a B cell with a CD40L expressing cell in the presence of IL-2 and IL-21 of Kitamura with a reasonable expectation of success. Since Kitamura suggests a rabbit B cell and a CD40L derived from the same species may be used in the method ([0037], [0048]), one of ordinary skill in the art would have had a reason to choose a rabbit B cell and a rabbit CD40L as suggested by Kitamura.
In regard to the new limitation cultivating a single B-cell wherein the single B-cell was from a single deposited rabbit IgG+ B-cell and proliferated during cultivation, Kitamura teaches “the term “antigen-specific IgG-positive B cell population … is not limited by the number of cells. This term includes not only a case in which a plurality of cells are present, but also a case in which only a single cell is present” ([0081]), thus clearly contemplates using the method for cultivating a single antigen-specific IgG+ B cell. Kitamura teaches the method comprises screening for antigen-specific B cells specific to the specific antigen (e.g., [0012]).
Furthermore, Tiller summarizes single B cell antibody technologies and their use for the discovery of monoclonal antibodies (mAbs) with potential therapeutic values or in basic research (abstract). Tiller teaches methods of single B cell isolation by, e.g., FACS (p. 454, left col, last section “Identification and isolation of single B cells”) and teaches antibody-secreting cells are of special interest (p. 454, right col, para 1). Tiller further teaches a method for screening B cells by developing the B cells into antibody-secreting cells and depositing the cells individually into an array of microscale wells on a chip for antibody screening and subsequently analyzed by clonal expansion (p. 454, right col, para 2). Thus, Tiller teaches a method for cultivating a single antibody-secreting B cell wherein the single B cell was from a single deposited antibody-secreting B cell and proliferated during cultivation.
Therefore, it would have been obvious for one of ordinary skill in the art before the date of the claimed invention being made to have modified the method of Kitamura, by choosing to cultivate a single antibody-secreting B cell wherein the single B cell was from a single deposited antibody-secreting B cell and proliferated during cultivation as suggested by Tiller with a reasonable expectation of success. Since Kitamura contemplates cultivating a single antigen-specific IgG-positive B cell ([0081]) and teaches screening for antigen-specific B cells ([0012]), and since Tiller teaches a method for screening antibody-secreting B cells by depositing the cells individually into an array of microscale wells on a chip for antibody screening and subsequent clonal expansion (p. 454, right col, para 2), and the use for the discovery of mAbs with potential therapeutic values or in basic research (abstract), one of ordinary skill in the art would have had a reason to choose to cultivate a single antibody-secreting B cell from a single deposited B cell and to proliferate the single B cell as suggested by Tiller in order to screen for antigen-specific single B cell clones for the discovery of mAbs with potential therapeutic values or in basic research.
However, Kitamura and Tiller are silent on a CHO cell expressing the CD40L.
Blair teaches a method for coculturing B cells with CD40 stimulation (see e.g., abstract). Blair teaches B cells are co-cultured with Chinese hamster ovary (CHO) cells that had been transfected with CD154 (CHO-CD154) and had been irradiated before co-culturing (p. 131, right col, para 1 and p. 138, left col, last para “Cell Culture”, it is noted that CD154 is also known as CD40L, and CHO cells are derived from epithelial cells of the ovary of the Chinese hamster), thus teaches a CHO cell expressing CD40L that can be irradiated and be used to coculture with B cells.
Therefore, it would have been obvious for one of ordinary skill in the art before the date of the claimed invention was made to have modified the method for producing an antibody comprising co-cultivating B cells with CD40L expressing cells such as epithelial cells suggested by Kitamura in view of Tiller, by choosing a CHO cell that expresses CD40L as suggested by Blair with a reasonable expectation of success. Since Kitamura suggests the CD40L expressing cells include epithelial cells ([0052]) and since Blair reduces to practice a CHO cell (derived from epithelial cells of the ovary of the Chinese hamster) that had been transfected with CD40L and had been irradiated for coculturing with B cells (p. 131, right col, para 1 and p. 138, left col, last para “Cell Culture”), one of ordinary skill in the art would have had a reason to choose a CHO cell expressing CD40L to coculture with B cells as suggested by Kitamura and Blair.
In regard to the new limitation wherein the rabbit CD40L is a heterologous protein and the feeder cell only expresses a single heterologous protein, Kitamura teaches a CD40L expression vector was introduced into feeder cells ([0098]), thus teaches the rabbit CD40L is a heterologous (i.e., exogenous) protein. Kitamura teaches “CD40L, BAFF or FasL is preferably in the form of being presented on the surface of a carrier” and “the carrier is preferably a cell” ([0051]-[0052]), thus teaches a feeder cell expressing either one of the molecules, including CD40L. Kitamura teaches “It is to be noted that CD40L, BAFF, FasL and an antigen may not be necessarily present on a single feeder cell”([0058]) and separated antigen presentation is “more efficiently than in the case of simultaneous introduction of all molecules” ([0094]), thus suggests the feeder cell only expresses a single heterologous protein separately.
Therefore, it would have been obvious for one of ordinary skill in the art before the date of the claimed invention was made to have chosen a heterologous CD40L protein and have chosen the feeder cell only expressing a single heterologous protein as suggested by Kitamura with a reasonable expectation of success. Since Kitamura has reduced to practice a method of introducing a heterologous CD40L protein into the feeder cells, and suggests a feeder cell expressing a single heterologous protein, including CD40L, separately (see above), one of ordinary skill in the art would have had a reason to choose a heterologous CD40L protein and choose the feeder cell only expressing a single heterologous protein as suggested by Kitamura in order to provide separate intracellular signals to IgG-positive B cells without simultaneous introduction of all molecules ([0094]).
With respect to claim 3 directed to a human IL-2 and a murine IL-21, Kitamura teaches examples of the origin of IL-21 … is preferably derived from rodents and mammals, and examples thereof include mice and humans ([0059]), thus suggests cytokines can be derived from mice and human. Kitamura teaches in Example 5 that a human IL-2 and a human IL-21 are used in coculturing B cells ([0120]) and in Example 1 a mouse IL-4 is used ([0100]).
Accordingly, it would have been obvious for one of ordinary skill in the art before the date of the claimed invention was made to have chosen a human IL-2 and a murine IL-21 with a reasonable expectation of success. Since Kitamura suggests cytokines such as IL-21 can be derived from mice and human and teaches in Example 5 that a human IL-2 and a human IL-21 are used, and since a mouse IL-21 and a human IL-21 have similar function and are for the same purpose (i.e., capable of stimulating IgG-positive B cells to grow, see [0060]), the murine IL-21 and human IL-21 are art-recognized obvious equivalents to each other. Therefore, it would have been obvious for one of ordinary skill in the art to have chosen a murine IL-21 in combination with a human IL-2 in the method of Kitamura. See MPEP 2144.06.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 12/16/2025 are acknowledged.
Applicant first argues that Kitamura recited in the prior Office action is referred to a B cell population, while the amended claims are now directed to a single antibody secreting IgG+ B cell (Remarks, p. 8).
Applicant’s arguments have been fully considered and they are persuasive. Therefore, the prior rejection has been withdrawn. However, as necessitated by amendment, a new ground of rejection has been made over Kitamura in view of Tiller and Blair. Specifically, Kitamura contemplates cultivating a single antigen-specific IgG-positive B cell and teaches screening for antigen-specific B cells, and Tiller teaches a method for screening antibody-secreting B cells by depositing the cells individually into an array of microscale wells on a chip for antibody screening and subsequent clonal expansion (see discussion above).
Applicant further argues that Kitamura’s method requires the use of a B cell population cultured in the presence of the specific antigen, CD40L, BAFF and FasL for the system to work, i.e., at least five components. Also Kitamura discloses use feeder cells that are modified to heterologously express CD40L, BAFF, FasL and the specific antigen (Remarks, p. 8, para 3).
Applicant’s arguments have been fully considered but they are not persuasive. As stated supra, Kitamura teaches “CD40L, BAFF or FasL is preferably in the form of being presented on the surface of a carrier” and “the carrier is preferably a cell” ([0051]-[0052], emphasis added), thus teaches a feeder cell expressing either one of the molecules, including CD40L. Kitamura teaches “It is to be noted that CD40L, BAFF, FasL and an antigen may not be necessarily present on a single feeder cell”([0058], emphasis added) and separated antigen presentation is “more efficiently than in the case of simultaneous introduction of all molecules” ([0094], emphasis added), thus suggests the feeder cell only expresses a single heterologous protein separately.
In regard to Kitamura’s method requiring at least five components to work, it is noted that the instant invention claims a method “comprising” the step and components. Applicant is reminded that the transitional term “comprising” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See MPEP 2111.03 (I). Therefore, the instant invention encompasses Kitamura’s method that requires at least five components to work.
Applicant finally argues that the currently pending claims describe a simplified improved method for the co-cultivation of rabbit B-cells with mammalian feeder cells expressing rabbit CD40L in the presence of IL-2 and IL-21 such that it improves B-cell growth characteristics of a single deposited cell, results in a rabbit B cell that grows more rapidly to a high cell density and produces higher IgG concentrations within a short time as compared to a rabbit B cell grown without CD40L expressing feeder cells and IL-2 and IL-21 (Remarks, p. 8, last full para).
Applicant’s arguments have been fully considered but they are not persuasive. MPEP § 2145 states that a showing of improved results must be based on evidence, not argument or speculation. In re Mayne, 104 F.3d 1339, 1343-44, 41 USPQ2d 1451, 1455-56 (Fed. Cir. 1997) (conclusory statements that claimed compound possesses unusually low immune response or unexpected biological activity that is unsupported by comparative data held insufficient to overcome prima facie case of obviousness).
In the instant case, the closest prior art Kitamura teaches a method for co-cultivation of an antigen-specific IgG+ B-cell (e.g., a rabbit B cell) with mammalian feeder cells expressing CD40L (e.g., rabbit CD40L) in the presence of IL-2 and IL-21, such that IgG-positive B cells are allowed to grow in large quantities ([0065]) and a monoclonal antibody against a specific antigen can be simply and rapidly obtained ([0087]). Thus, Applicant’s results are expected by Kitamura.
Claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over Kitamura et al., (WO2011052545A1, published 05/05/2011. Cited in IDS 04/13/2023. The corresponding US patent publication US2012/0214192 is referred to hereinafter as “Kitamura” in consistent with Applicant’s remarks) in view of Tiller (N Biotechnol. 2011; 28(5): 453-457) and Blair et al., (Immunity. 2010; 32: 129-140. Prior art of record), as applied to claim 1 above, and further in view of Hirano et al., (Proc Natl Acad Sci USA. 1985; 82(16): 5490-5494).
Claim 30 is directed to cultivating in the presence of IL-6.
However, Kitamura, Tiller and Blair are silent on IL-6.
Hirano purifies B cell differentiation factor (BCDF, also known as IL-6) and teaches purified BCDF induces IgG production in B cell line (p. 5492, left col, last para and see Fig 3B).
Therefore, it would have been obvious for one of ordinary skill in the art before the date of the claimed invention was made to have combined IL-6 in the culture as suggested by Hirano with a reasonable expectation of success. Since Kitamura teaches other cytokines may be used together with IL-21, such as IL-2 (e.g., [0076]), and since Hirano teaches BCDF (IL-6) induces IgG antibody production in B cell line (e.g., Fig 3B), one of ordinary skill in the art would have had a reason to combine IL-6 in cultivating the antibody-secreting IgG+ B cell in order to increase antibody production.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 12/16/2025 are acknowledged and have been discussed above.
Claims 8 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Kitamura et al., (WO2011052545A1, published 05/05/2011. Cited in IDS 04/13/2023. The corresponding US patent publication US2012/0214192 is referred to hereinafter as “Kitamura” in consistent with Applicant’s remarks) in view of Tiller (N Biotechnol. 2011; 28(5): 453-457) and Popma et al., (International Immunopharmacology. 2005; 5: 155-162. Prior art of record).
With respect to independent claim 8, Kitamura teaches a method for producing an antigen-specific B cell population which contains IgG-positive B cells that are specific to a particular antigen (see e.g., abstract), thus teaches a method for cultivating a B cell secreting an antibody that specifically binds to a particular antigen.
In regard to the step of co-cultivating a rabbit antibody secreting IgG+ B cell with a rabbit CD40L expressing cell in the presence of IL-2 and IL-21, Kitamura teaches IgG-positive B cells are cultured together with the particular antigen in the presence of IL-21, while providing the IgG-positive B cells with stimulation through CD40 (see e.g., abstract). Kitamura teaches the B cell population used in the present invention may be a cell population derived from an organism with an established immune system, such as … Mammalian rodents such as … rabbits ([0037]), thus suggests a rabbit B cell. Kitamura teaches examples of the origin of CD40L, … include … small mammal rodents… it may be derived from the same species as the cell population to be presented ([0048]), thus suggests a rabbit CD40L to culture with a rabbit B cell. Kitamura teaches the CD40L expressing cells include fibroblasts, epithelial cells, fetal kidney cells, and follicular dendritic cells ([0052]) and uses irradiated 3T3 cells ([0098]). Kitamura teaches other cytokines may be used together with IL-21, for example, when IL-2 is used in combination with IL-21, the concentration of IL-2 is preferably 1 ng/ml to 1 μg/ml (e.g., [0076], also see Example 5 in [0120]), thus teaches coculturing B cells in the presence of IL-2 and IL-21.
Accordingly, it would have been obvious for one of ordinary skill in the art before the date of the claimed invention being made to have chosen a rabbit B cell and a rabbit CD40L in the method of co-cultivating a B cell with a CD40L expressing cell in the presence of IL-2 and IL-21 of Kitamura with a reasonable expectation of success. Since Kitamura suggests a rabbit B cell and a CD40L derived from the same species may be used in the method ([0037], [0048]), one of ordinary skill in the art would have had a reason to choose a rabbit B cell and a rabbit CD40L as suggested by Kitamura.
In regard to the new limitation cultivating a single B-cell wherein the single B-cell was from a single deposited rabbit IgG+ B-cell and proliferated during cultivation, Kitamura teaches “the term “antigen-specific IgG-positive B cell population … is not limited by the number of cells. This term includes not only a case in which a plurality of cells are present, but also a case in which only a single cell is present” ([0081]), thus clearly contemplates using the method for cultivating a single antigen-specific IgG+ B cell. Kitamura teaches the method comprises screening for antigen-specific B cells specific to the specific antigen (e.g., [0012]).
Furthermore, Tiller summarizes single B cell antibody technologies and their use for the discovery of monoclonal antibodies (mAbs) with potential therapeutic values or in basic research (abstract). Tiller teaches methods of single B cell isolation by, e.g., FACS (p. 454, left col, last section “Identification and isolation of single B cells”) and teaches antibody-secreting cells are of special interest (p. 454, right col, para 1). Tiller further teaches a method for screening B cells by developing the B cells into antibody-secreting cells and depositing the cells individually into an array of microscale wells on a chip for antibody screening and subsequently analyzed by clonal expansion (p. 454, right col, para 2). Thus, Tiller teaches a method for cultivating a single antibody-secreting B cell wherein the single B cell was from a single deposited antibody-secreting B cell and proliferated during cultivation.
Therefore, it would have been obvious for one of ordinary skill in the art before the date of the claimed invention being made to have modified the method of Kitamura, by choosing to cultivate a single antibody-secreting B cell wherein the single B cell was from a single deposited antibody-secreting B cell and proliferated during cultivation as suggested by Tiller with a reasonable expectation of success. Since Kitamura contemplates cultivating a single antigen-specific IgG-positive B cell ([0081]) and teaches screening for antigen-specific B cells ([0012]), and since Tiller teaches a method for screening antibody-secreting B cells by depositing the cells individually into an array of microscale wells on a chip for antibody screening and subsequent clonal expansion (p. 454, right col, para 2), and the use for the discovery of mAbs with potential therapeutic values or in basic research (abstract), one of ordinary skill in the art would have had a reason to choose to cultivate a single antibody-secreting B cell from a single deposited B cell and to proliferate the single B cell as suggested by Tiller in order to screen for antigen-specific single B cell clones for the discovery of mAbs with potential therapeutic values or in basic research.
However, Kitamura is silent on the antibody that specifically binds to a T cell surface antigen and that mediates a negative stimulus to T cells in claim 8.
Popma teaches an anti-CD3 antibody that induces proliferation of T cells but impairs expansion of alloreactive T cells that can be used to reverse acute transplant rejection (e.g., abstract). Popma teaches the anti-CD3 antibody, such as OKT3, target CD3 epitopes on T cells (p. 156, para 1), and inhibits the logarithmic expansion of allo-reactive T cells (e.g., abstract). Thus, Popma teaches an antibody that specifically binds to a T cell surface antigen (i.e., CD3 epitope) and that mediates a negative stimulus to T cells (i.e., inhibits expansion of alloreactive T cells).
Therefore, it would have been obvious for one of ordinary skill in the art before the date of the claimed invention was made to have modified the method suggested by Kitamura, by choosing an antibody that specifically binds to a T cell surface antigen CD3 and that mediates a negative stimulus to T cells suggested by Popma with a reasonable expectation of success. Since Kitamura suggests the antibodies may bind to an “antigen of interest” ([0028]) including a variety of antigens ([0055]), and since Popma teaches an anti-CD3 antibody specifically binds to a T cell surface antigen CD3 and mediates a negative stimulus to alloreactive T cells to reverse acute transplant rejection (e.g., abstract), one of ordinary skill in the art would have had a reason to choose an anti-CD3 antibody suggested by Popma in order to produce anti-CD3 antibodies to treat acute transplant rejection (see Popma, abstract).
In regard to the new limitation wherein the rabbit CD40L is a heterologous protein and the feeder cell only expresses a single heterologous protein, Kitamura teaches a CD40L expression vector was introduced into feeder cells ([0098]), thus teaches the rabbit CD40L is a heterologous (i.e., exogenous) protein. Kitamura teaches “CD40L, BAFF or FasL is preferably in the form of being presented on the surface of a carrier” and “the carrier is preferably a cell” ([0051]-[0052]), thus teaches a feeder cell expressing either one of the molecules, including CD40L. Kitamura teaches “It is to be noted that CD40L, BAFF, FasL and an antigen may not be necessarily present on a single feeder cell”([0058]) and separated antigen presentation is “more efficiently than in the case of simultaneous introduction of all molecules” ([0094]), thus suggests the feeder cell only expresses a single heterologous protein separately.
Therefore, it would have been obvious for one of ordinary skill in the art before the date of the claimed invention was made to have chosen a heterologous CD40L protein and have chosen the feeder cell only expressing a single heterologous protein as suggested by Kitamura with a reasonable expectation of success. Since Kitamura has reduced to practice a method of introducing a heterologous CD40L protein into the feeder cells, and suggests a feeder cell expressing a single heterologous protein, including CD40L, separately (see above), one of ordinary skill in the art would have had a reason to choose a heterologous CD40L protein and choose the feeder cell only expressing a single heterologous protein as suggested by Kitamura in order to provide separate intracellular signals to IgG-positive B cells without simultaneous introduction of all molecules ([0094]).
With respect to claim 31 directed to a human IL-2 and a murine IL-21, Kitamura teaches examples of the origin of IL-21 … is preferably derived from rodents and mammals, and examples thereof include mice and humans ([0059]), thus suggests cytokines can be derived from mice and human. Kitamura teaches in Example 5 that a human IL-2 and a human IL-21 are used in coculturing B cells ([0120]) and in Example 1 a mouse IL-4 is used ([0100]).
Accordingly, it would have been obvious for one of ordinary skill in the art before the date of the claimed invention was made to have chosen a human IL-2 and a murine IL-21 with a reasonable expectation of success. Since Kitamura suggests cytokines such as IL-21 can be derived from mice and human and teaches in Example 5 that a human IL-2 and a human IL-21 are used, and since a mouse IL-21 and a human IL-21 have similar function and are for the same purpose (i.e., capable of stimulating IgG-positive B cells to grow, see [0060]), the murine IL-21 and human IL-21 are art-recognized obvious equivalents to each other. Therefore, it would have been obvious for one of ordinary skill in the art to have chosen a murine IL-21 in combination with a human IL-2 in the method of Kitamura. See MPEP 2144.06.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 12/16/2025 are acknowledged and have been discussed above.
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Kitamura et al., (WO2011052545A1, published 05/05/2011. Cited in IDS 04/13/2023. The corresponding US patent publication US2012/0214192 is referred to hereinafter as “Kitamura” in consistent with Applicant’s remarks) in view of Tiller (N Biotechnol. 2011; 28(5): 453-457) and Popma et al., (International Immunopharmacology. 2005; 5: 155-162. Prior art of record), as applied to claim 8 above, and further in view of Hirano et al., (Proc Natl Acad Sci USA. 1985; 82(16): 5490-5494).
Claim 32 is directed to cultivating in the presence of IL-6.
However, Kitamura, Tiller and Popma are silent on IL-6.
Hirano purifies B cell differentiation factor (BCDF, also known as IL-6) and teaches purified BCDF induces IgG production in B cell line (p. 5492, left col, last para and see Fig 3B).
Therefore, it would have been obvious for one of ordinary skill in the art before the date of the claimed invention was made to have combined IL-6 in the culture as suggested by Hirano with a reasonable expectation of success. Since Kitamura teaches other cytokines may be used together with IL-21, such as IL-2 (e.g., [0076]), and since Hirano teaches BCDF (IL-6) induces IgG antibody production in B cell line (e.g., Fig 3B), one of ordinary skill in the art would have had a reason to combine IL-6 in cultivating the antibody-secreting IgG+ B cell in order to increase antibody production.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 12/16/2025 are acknowledged and have been discussed above.
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Kitamura et al., (WO2011052545A1, published 05/05/2011. Cited in IDS 04/13/2023. The corresponding US patent publication US2012/0214192 is referred to hereinafter as “Kitamura” in consistent with Applicant’s remarks) in view of Tiller (N Biotechnol. 2011; 28(5): 453-457) and Popma et al., (International Immunopharmacology. 2005; 5: 155-162. Prior art of record), as applied to claim 8 above, and further in view of Blair et al., (Immunity. 2010; 32: 129-140. Prior art of record).
Claim 33 is directed to the mammalian cell being a CHO cell.
However, Kitamura, Tiller and Popma are silent on a CHO cell.
Blair teaches a method for coculturing B cells with CD40 stimulation (see e.g., abstract). Blair teaches B cells are co-cultured with Chinese hamster ovary (CHO) cells that had been transfected with CD154 (CHO-CD154) and had been irradiated before co-culturing (p. 131, right col, para 1 and p. 138, left col, last para “Cell Culture”, it is noted that CD154 is also known as CD40L, and CHO cells are derived from epithelial cells of the ovary of the Chinese hamster), thus teaches a CHO cell expressing CD40L that can be irradiated and be used to coculture with B cells.
Therefore, it would have been obvious for one of ordinary skill in the art before the date of the claimed invention was made to have chosen a CHO cell that expresses CD40L as suggested by Blair with a reasonable expectation of success. Since Kitamura suggests the CD40L expressing cells include epithelial cells ([0052]) and since Blair reduces to practice a CHO cell (derived from epithelial cells of the ovary of the Chinese hamster) that had been transfected with CD40L and had been irradiated for coculturing with B cells (p. 131, right col, para 1 and p. 138, left col, last para “Cell Culture”), one of ordinary skill in the art would have had a reason to choose a CHO cell expressing CD40L to coculture with B cells as suggested by Kitamura and Blair.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 12/16/2025 are acknowledged and have been discussed above.
Claims 9-11 are rejected under 35 U.S.C. 103 as being unpatentable over Kitamura et al., (WO2011052545A1, published 05/05/2011. Cited in IDS 04/13/2023. The corresponding US patent publication US2012/0214192 is referred to hereinafter as “Kitamura” in consistent with Applicant’s remarks) in view of Tiller (N Biotechnol. 2011; 28(5): 453-457).
With respect to independent claim 9, Kitamura teaches a method for producing an antigen-specific B cell population which contains IgG-positive B cells that are specific to a particular antigen by coculturing the B cells with IL-21 and CD40L expressing cells (see e.g., abstract), thus teaches a method for the cultivation of an antibody secreting B cell.
In regard to the two culture steps in claim 9 (i) and (ii), Kitamura teaches in Example 1 section (3) that the culture process comprises a “primary culture” of the B cell on a CD40L expressing mammalian cell (3T3 cells) in the presence of a mitogenic stimulant, i.e., an IL-4 (see [0100]), related to claim 9 step (i) and claim 10, and Kitamura teaches a “secondary culture” of the B cells on the newly prepared CD40L expressing mammalian cells in the presence of an antibody production stimulant, i.e., IL-21 (see [0101]), related to claim 9 step (ii) and claim 11.
In regard a rabbit B cell and a rabbit CD40L in claim 9, Kitamura teaches the B cell population used in the present invention may be a cell population derived from an organism with an established immune system, such as … Mammalian rodents such as … rabbits ([0037]), thus suggests a rabbit B cell. Kitamura teaches examples of the origin of CD40L, … include … small mammal rodents… it may be derived from the same species as the cell population to be presented ([0048]), thus suggests a rabbit CD40L to culture with a rabbit B cell.
Accordingly, it would have been obvious for one of ordinary skill in the art before the date of the claimed invention was made to have chosen a rabbit B cell and a rabbit CD40L in the method of Kitamura with a reasonable expectation of success. Since Kitamura suggests a rabbit B cell and a CD40L derived from the same species may be used in the method ([0037], [0048]), one of ordinary skill in the art would have had a reason to choose a rabbit B cell and a rabbit CD40L as suggested by Kitamura.
In regard to the new limitation cultivating a single B-cell wherein the single B-cell was from a single deposited rabbit IgG+ B-cell and proliferated during cultivation, Kitamura teaches “the term “antigen-specific IgG-positive B cell population … is not limited by the number of cells. This term includes not only a case in which a plurality of cells are present, but also a case in which only a single cell is present” ([0081]), thus clearly contemplates cultivating a single antigen-specific IgG+ B cell. Kitamura teaches the method comprises screening for antigen-specific B cells (e.g., [0012]).
Furthermore, Tiller summarizes single B cell antibody technologies and their use for the discovery of monoclonal antibodies (mAbs) with potential therapeutic values or in basic research (abstract). Tiller teaches methods of single B cell isolation by, e.g., FACS (p. 454, left col, last section “Identification and isolation of single B cells”) and teaches antibody-secreting cells are of special interest (p. 454, right col, para 1). Tiller further teaches a method for screening B cells by developing the B cells into antibody-secreting cells and depositing the cells individually into an array of microscale wells on a chip for antibody screening and subsequently analyzed by clonal expansion (p. 454, right col, para 2). Thus, Tiller teaches a method for cultivating a single antibody-secreting B cell wherein the single B cell was from a single deposited antibody-secreting B cell and proliferated during cultivation.
Therefore, it would have been obvious for one of ordinary skill in the art before the date of the claimed invention being made to have modified the method of Kitamura, by choosing to cultivate a single antibody-secreting B cell wherein the single B cell was from a single deposited antibody-secreting B cell and proliferated during cultivation as suggested by Tiller with a reasonable expectation of success. Since Kitamura contemplates cultivating a single antigen-specific IgG-positive B cell ([0081]) and teaches screening for antigen-specific B cells ([0012]), and since Tiller teaches a method for screening antibody-secreting B cells by depositing the cells individually into an array of microscale wells on a chip for antibody screening and subsequent clonal expansion (p. 454, right col, para 2), and the use for the discovery of mAbs with potential therapeutic values or in basic research (abstract), one of ordinary skill in the art would have had a reason to choose to cultivate a single antibody-secreting B cell from a single deposited B cell and to proliferate the single B cell as suggested by Tiller in order to screen for antigen-specific single B cell clones for the discovery of mAbs with potential therapeutic values or in basic research.
In regard to the new limitation wherein the rabbit CD40L is a heterologous protein and the feeder cell only expresses a single heterologous protein, Kitamura teaches a CD40L expression vector was introduced into feeder cells ([0098]), thus teaches the rabbit CD40L is a heterologous (i.e., exogenous) protein. Kitamura teaches “CD40L, BAFF or FasL is preferably in the form of being presented on the surface of a carrier” and “the carrier is preferably a cell” ([0051]-[0052]), thus teaches a feeder cell expressing either one of the molecules, including CD40L. Kitamura teaches “It is to be noted that CD40L, BAFF, FasL and an antigen may not be necessarily present on a single feeder cell”([0058]) and separated antigen presentation is “more efficiently than in the case of simultaneous introduction of all molecules” ([0094]), thus suggests the feeder cell only expresses a single heterologous protein separately.
Therefore, it would have been obvious for one of ordinary skill in the art before the date of the claimed invention was made to have chosen a heterologous CD40L protein and have chosen the feeder cell only expressing a single heterologous protein as suggested by Kitamura with a reasonable expectation of success. Since Kitamura has reduced to practice a method of introducing a heterologous CD40L protein into the feeder cells, and suggests a feeder cell expressing a single heterologous protein, including CD40L, separately (see above), one of ordinary skill in the art would have had a reason to choose a heterologous CD40L protein and choose the feeder cell only expressing a single heterologous protein as suggested by Kitamura in order to provide separate intracellular signals to IgG-positive B cells without simultaneous introduction of all molecules ([0094]).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 12/16/2025 are acknowledged and have been discussed above.
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Kitamura et al., (WO2011052545A1, published 05/05/2011. Cited in IDS 04/13/2023. The corresponding US patent publication US2012/0214192 is referred to hereinafter as “Kitamura” in consistent with Applicant’s remarks) in view of Tiller (N Biotechnol. 2011; 28(5): 453-457), as applied to claim 9 above, and further in view of Blair et al., (Immunity. 2010; 32: 129-140. Prior art of record).
Claim 34 is directed to the mammalian cell being a CHO cell.
However, Kitamura and Tiller are silent on a CHO cell.
Blair teaches a method for coculturing B cells with CD40 stimulation (see e.g., abstract). Blair teaches B cells are co-cultured with Chinese hamster ovary (CHO) cells that had been transfected with CD154 (CHO-CD154) and had been irradiated before co-culturing (p. 131, right col, para 1 and p. 138, left col, last para “Cell Culture”, it is noted that CD154 is also known as CD40L, and CHO cells are derived from epithelial cells of the ovary of the Chinese hamster), thus teaches a CHO cell expressing CD40L that can be irradiated and be used to coculture with B cells.
Therefore, it would have been obvious for one of ordinary skill in the art before the date of the claimed invention was made to have chosen a CHO cell that expresses CD40L as suggested by Blair with a reasonable expectation of success. Since Kitamura suggests the CD40L expressing cells include epithelial cells ([0052]) and since Blair reduces to practice a CHO cell (derived from epithelial cells of the ovary of the Chinese hamster) that had been transfected with CD40L and had been irradiated for coculturing with B cells (p. 131, right col, para 1 and p. 138, left col, last para “Cell Culture”), one of ordinary skill in the art would have had a reason to choose a CHO cell expressing CD40L to coculture with B cells as suggested by Kitamura and Blair.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 12/16/2025 are acknowledged and have been discussed above.
Maintained Double Patenting Rejections
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 3, 8-11 and 30-34 are rejected on the ground of nonstatutory double patenting as being unpatentable over patented claims of US Patent Nos: 10,889,802 or 11,952,586, in view of Kitamura et al., (WO2011052545A1, published 05/05/2011. English translation from Google Patent. Cited in IDS 04/13/2023), Blair et al., (Immunity. 2020; 32: 129-140. Prior art of record) and Popma et al., (Intl Immunopharmacology. 2005; 5: 155-162. Prior art of record). Although the claims at issue are not identical, they are not patentably distinct from each other.
It is noted that the prior rejection of claims 1, 3 and 8-11 are maintained.
Claims in the cited patents recite a method for co-cultivating one or more B-cells comprising the steps of incubating the one or more B-cells with an aliquot of the EL4-B5 cells, wherein the incubating is additionally in the presence of a feeder mix, wherein the feeder mix comprises one or more of: iv) interleukin-21 (IL-21), interleukin-2 (IL-2), and IL-6, wherein the EL4-B5 cells are, after the cultivating and prior to the incubating, irradiated with y-radiation, wherein the one B-cell is a single deposited B-cell, a method for producing an antibody, the method comprising performing the method according to claim 1, thereby producing the antibody.
However, cited patented claims do not recite a rabbit B cell or a rabbit CD40L, the CD40L expressing cells (i.e., the EL4-B5 cells) being CHO cells only expressing a single heterologous protein, the IL-2 being human IL-2 and the IL-21 being murine IL-21, or the antibody specifically binding to a T cell surface antigen and mediating a negative stimulus to T cells.
In regard a rabbit B cell and a rabbit CD40L, Kitamura teaches the B cell population used in the present invention may be a cell population derived from an organism with an established immune system, such as … Mammalian rodents such as … rabbits (p. 3, lines 1-2), thus suggests a rabbit B cell. Kitamura teaches examples of the origin of CD40L, … include … small mammal rodents… it may be derived from the same species as the cell population to be presented (p. 3, para 9), thus suggests a rabbit CD40L to culture with a rabbit B cell. In regard to a human IL-2 and a murine IL-21, Kitamura teaches examples of the origin of IL-21 … is preferably derived from rodents and mammals, and examples thereof include mice and humans (p. 4, para 4), thus suggests cytokines can be derived from mice and human. Kitamura teaches in Example 5 that a human IL-2 and a human IL-21 are used in coculturing B cells (p. 7, para 3) and in Example 1 a mouse IL-4 is used (p. 6, para 2). In regard to the new limitation wherein the rabbit CD40L is a heterologous protein and the feeder cell only expresses a single heterologous protein, Kitamura teaches a CD40L expression vector was introduced into feeder cells ([0098]). Kitamura teaches “CD40L, BAFF or FasL is preferably in the form of being presented on the surface of a carrier” and “the carrier is preferably a cell” ([0051]-[0052]), thus teaches a feeder cell expressing either one of the molecules, including CD40L. Kitamura teaches “It is to be noted that CD40L, BAFF, FasL and an antigen may not be necessarily present on a single feeder cell”([0058]) and separated antigen presentation is “more efficiently than in the case of simultaneous introduction of all molecules” ([0094]), thus suggests the feeder cell only expresses a single heterologous protein separately.
In regard to a CHO cell expressing the CD40L, Blair teaches a method for coculturing B cells with CD40 stimulation (see e.g., abstract). Blair teaches B cells are co-cultured with Chinese hamster ovary (CHO) cells that had been transfected with CD154 (CHO-CD154) and had been irradiated before co-culturing (p. 131, right col, para 1 and p. 138, left col, last para “Cell Culture”, it is noted that CD154 is also known as CD40L, and CHO cells are derived from epithelial cells of the ovary of the Chinese hamster), thus teaches a CHO cell expressing CD40L that can be irradiated and be used to coculture with B cells and the CHO cell only expresses a single heterologous protein.
In regard to the antibody binding to a T cell surface antigen, Popma teaches an anti-CD3 antibody that induces proliferation of T cells but impairs expansion of alloreactive T cells that can be used to reverse acute transplant rejection (e.g., abstract). Popma teaches the anti-CD3 antibody, such as OKT3, target CD3 epitopes on T cells (p. 156, para 1), and inhibits the logarithmic expansion of allo-reactive T cells (e.g., abstract). Thus, Popma teaches an antibody that specifically binds to a T cell surface antigen (i.e., CD3 epitope) and that mediates a negative stimulus to T cells (i.e., inhibits expansion of alloreactive T cells).
Therefore, it would have been obvious for one of ordinary skill in the art before the date of the claimed invention was made to have modified the method recited in the Patents, by choosing a rabbit B cell and a rabbit CD40L and choosing a human IL-2 and a murine IL-21 as suggested by Kitamura, by substituting the CD40L-expressing EL4-B5 cells with a CHO cell expressing CD40L as suggested by Blair, and by choosing an anti-CD3 antibody as suggested by Popma with a reasonable expectation of success. Since Kitamura suggests a rabbit B cells and a rabbit CD40L as well as a human IL-2 and a murine IL-21 may be used in the method of co-culturing B cells to produce antibody, since Blair reduces to practice a CHO cell only expressing CD40L in B cell coculturing, and since Popma teaches an anti-CD3 antibody may be used to inhibit alloreactive T cell expansion to treat acute transplant rejection, one of ordinary skill in the art would have had a reason to make the modification to the claims in order to produce an antibody from rabbit B cells to treat acute transplant rejection.
Since the instant application claims are obvious over cited patent claims, in view of Kitamura, Blair and Popma, said claims are not patentably distinct.
Response to Traversal:
Applicant’s arguments filed on 12/16/2025 are acknowledged.
Applicant first argues that the non-statutory double patenting rejection is not proper because the reference patents have later expiration dates (p. 10).
Applicant’s arguments have been fully considered but they are not persuasive. Applicant is reminded that a complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims, or the filing of a terminal disclaimer. See MPEP 804.(I).B.1.
Applicant further argues that using a secondary reference Kitamura to support a reason of obviousness is improper (Remarks, p. 11).
Applicant’s arguments have been fully considered but they are not persuasive. As stated supra, the prior, and the instant, nonstatutory double patenting rejection provides comparison between the cited patent claims and the instant claims, and provides the reasons why the instant invention would have been obvious to an ordinary skill in the art. Furthermore, second references, such as Kitamura, are used to support an obviousness analysis (see above).
Applicant finally argues that the cited patent claims fail to teach or even suggest a method reciting a rabbit CD40L expressing mammalian cell, the rabbit CD40L is a heterologous protein and the mammalian cell only expresses a single heterologous protein. Applicant also argues that Kitamura and the remaining cited references fail to teach or suggest a single antibody secreting rabbit IgG+ B cell (Remarks p. 11-12).
Applicant’s arguments have been fully considered but they are not persuasive. Applicant is reminded, 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 the instant case, the patent claims in the cited reference patents recite a single antibody secreting B cell from a single deposited B-cell (see claims 1, 7 or 9 of the reference claims). The differences between the cited reference patent claims and the instant claims are that the cited references claims are silent on a rabbit IgG+ B cell, a rabbit CD40L, or the rabbit CD40L being a heterologous protein, or the mammalian cell only expressing a single heterologous protein. Prior art Kitamura, Blair and Popma are cited to make obvious these limitations as discussed above.
Therefore, Applicant’s arguments are not persuasive thus the prior rejection is maintained.
Claims 1, 3, 8-11 and 30-34 are rejected on the ground of nonstatutory double patenting as being unpatentable over patented claims 1, 8-9 and 13 of US Patent No: 12,378,315, in view of Kitamura et al., (WO2011052545A1, published 05/05/2011. English translation from Google Patent. Cited in IDS 04/13/2023), Blair et al., (Immunity. 2020; 32: 129-140. Prior art of record) and Popma et al., (Intl Immunopharmacology. 2005; 5: 155-162. Prior art of record). Although the claims at issue are not identical, they are not patentably distinct from each other.
It is noted that the prior rejection of claims 1, 3 and 8-11 are maintained.
Claims in the cited patent recite a method for selecting a rabbit B cell comprising incubating the rabbit B cells with an anti-CD19 antibody of claim 1 (reference claim 8) to select B cells and co-cultivating the single depositing B cell with feeder cells (reference claim 9), wherein the co-cultivating is in the presence of a synthetic feeder mix that comprises IL-1β, TNFα, IL-10, and one or more selected from IL-21, SAC, BAFF, IL-2, IL-4, and IL-6 (reference claim 13). Thus, cited claims recite a method for co-cultivating a single deposited rabbit B cell with feeder cells in the presence of IL-2, IL-6 and IL-21.
However, cited claims do not recite the co-cultivating B cells produces antibody, a rabbit CD40L-expressing mammalian cell or CHO cell as the feeder cells, the IL-2 being human IL-2 and the IL-21 being murine IL-21, or the antibody specifically binding to a T cell surface antigen and mediating a negative stimulus to T cells.
Kitamura teaches co-cultivating B cells with CD40L-expressing mammalian cells in the presence of IL-2 and IL-21 produces antigen-specific B cells and antibodies (see abstract). Kitamura teaches in Example 1 section (3) that the culture process comprises a “primary culture” of the B cell on a CD40L expressing mammalian cell (3T3 cells, “40LB” feeder cells) in the presence of a mitogenic stimulant such as IL-4, thus teaches a CD40L-expressing mammalian cell as feeder cells. Kitamura teaches examples of the origin of CD40L, … include … small mammal rodents… it may be derived from the same species as the cell population to be presented (p. 3, para 9), thus suggests a rabbit CD40L to culture with a rabbit B cell. In regard to a human IL-2 and a murine IL-21, Kitamura teaches examples of the origin of IL-21 … is preferably derived from rodents and mammals, and examples thereof include mice and humans (p. 4, para 4), thus suggests cytokines can be derived from mice and human. Kitamura teaches in Example 5 that a human IL-2 and a human IL-21 are used in coculturing B cells (p. 7, para 3) and in Example 1 a mouse IL-4 is used (p. 6, para 2). In regard to the new limitation wherein the rabbit CD40L is a heterologous protein and the feeder cell only expresses a single heterologous protein, Kitamura teaches a CD40L expression vector was introduced into feeder cells ([0098]). Kitamura teaches “CD40L, BAFF or FasL is preferably in the form of being presented on the surface of a carrier” and “the carrier is preferably a cell” ([0051]-[0052]), thus teaches a feeder cell expressing either one of the molecules, including CD40L. Kitamura teaches “It is to be noted that CD40L, BAFF, FasL and an antigen may not be necessarily present on a single feeder cell”([0058]) and separated antigen presentation is “more efficiently than in the case of simultaneous introduction of all molecules” ([0094]), thus suggests the feeder cell only expresses a single heterologous protein separately.
In regard to a CHO cell expressing the CD40L, Blair teaches a method for coculturing B cells with CD40 stimulation (see e.g., abstract). Blair teaches B cells are co-cultured with Chinese hamster ovary (CHO) cells that had been transfected with CD154 (CHO-CD154) and had been irradiated before co-culturing (p. 131, right col, para 1 and p. 138, left col, last para “Cell Culture”, it is noted that CD154 is also known as CD40L, and CHO cells are derived from epithelial cells of the ovary of the Chinese hamster), thus teaches a CHO cell only expressing CD40L that can be irradiated and be used to coculture with B cells.
In regard to the antibody binding to a T cell surface antigen, Popma teaches an anti-CD3 antibody that induces proliferation of T cells but impairs expansion of alloreactive T cells that can be used to reverse acute transplant rejection (e.g., abstract). Popma teaches the anti-CD3 antibody target CD3 epitopes on T cells (p. 156, para 1), and inhibits the logarithmic expansion of allo-reactive T cells (e.g., abstract)..
Therefore, it would have been obvious for one of ordinary skill in the art before the date of the claimed invention was made to have modified the method recited in the Patent, by choosing a rabbit CD40L-expressing mammalian feeder cell and choosing a human IL-2 and a murine IL-21 to produce antibody as suggested by Kitamura, by choosing a CHO cell expressing CD40L as the feeder cell as suggested by Blair, and by choosing an anti-CD3 antibody as suggested by Popma with a reasonable expectation of success. Since Kitamura suggests a rabbit CD40L can be used with a rabbit B cell, as well as a human IL-2 and a murine IL-21 may be used in the method of co-culturing B cells to produce antibody, since Blair reduces to practice a CHO cell only expressing CD40L in B cell coculturing, and since Popma teaches an anti-CD3 antibody may be used to inhibit alloreactive T cell expansion to treat acute transplant rejection, one of ordinary skill in the art would have had a reason to make the modification to the claims in order to produce an antibody from rabbit B cells to treat acute transplant rejection.
Since the instant application claims are obvious over cited patent claims, in view of Kitamura, Blair and Popma, said claims are not patentably distinct.
Response to Traversal:
Applicant’s arguments filed on 12/16/2025 are acknowledged and have been discussed above.
Conclusion
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.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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/JIANJIAN ZHU/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631