Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Amendments
In the reply filed 11/17/2025, Applicant has amended Claims 1-3, 5, 12-13, 16, 18, 21, and 24, and added a new claim, Claims 34.
Claims 3, 32-33 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 1-2, 4-6, 10, 12-13, 16, 18-21, 24, 26, and 34 are under consideration.
Withdrawn Objections to the Specification
The prior objection to the disclosure because of the reference to color drawings is withdrawn in light of Applicant’s amended specification filed 11/17/2025. Furthermore, the prior object to the disclosure for containing illustrations is withdrawn in light of Applicant’s arguments.
Withdrawn Claim Objections
The prior objections to Claims 13 and 21 are withdrawn in light of Applicant’s amendments.
Withdrawn 35 USC § 112
The prior rejection of Claims 2, 5-6, 12, 13, 16, 18-19, and 24 under 35 U.S.C. § 112(b) pre-AIA 2nd paragraph as being indefinite is withdrawn in light of Applicant’s amendments of Claims 2 and 24 to describe the gene, amendments of Claims 5 and 16 to describe the guide RNA, arguments towards Claim 6 to describe about, amendments of Claim 12 to describe the delivery step, and Claim 13 to describe the electroporation step, and amendments of Claim 18 to describe the cytokine
.
Withdrawn 35 USC § 103
The prior rejection of Claims 1, 2, 10, 12-13, 18, 21, 24, and 26 under 35 U.S.C. 103 as being unpatentable over Moriarity et al. (US2022/0168342, filed 9/12/2017, published 6/02/2022), in view of Kim et al. (KR2017/0113961, filed 3/30/2016, published 10/13/2017) is withdrawn in light of Applicant’s amendment of Claim 1 to include step of transducing and culturing human B cells in IL-21.
The prior rejection of Claims 4-6 under 35 U.S.C. 103 as being unpatentable over Moriarity et al. (US2022/0168342, filed 9/12/2017, published 6/02/2022), in view of Kim et al. (KR2017/0113961, filed 3/30/2016, published 10/13/2017), as applied to claims 1 and 24, in further view of Cotta-Ramusino et al., (US 12,359,223, filed 1/30/2019, patented 7/15/2025) is withdrawn in light of Applicant’s amendment of Claim 1.
The prior rejection of Claims 16 and 19 under 35 U.S.C. 103 as being unpatentable over Moriarity et al. (US2022/0168342, filed 9/12/2017, published 6/02/2022), in view of Kim et al. (KR2017/0113961, filed 3/30/2016, published 10/13/2017), as applied to claims 1 and 18, in further view of Johnson et al., (Sci Reports, 2018, 8:12144, pgs. 3-9) is withdrawn in light of Applicant’s amendment of Claim 1.
The prior rejection of Claim 20 under 35 U.S.C. 103 as being unpatentable over Moriarity et al. (US2022/0168342, filed 9/12/2017, published 6/02/2022), in view of Kim et al. (KR2017/0113961, filed 3/30/2016, published 10/13/2017), as applied to claim 1, in further view of Scholz et al., (WO2016/100932, filed 12/18/2015, published 6/23/2016) is withdrawn in light of Applicant’s amendment of Claim 1.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 2, 10, 12-13, 18, 20, 21, 24, 26 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Moriarity et al. (US2022/0168342, filed 9/12/2017, published 6/02/2022, prior art of record), in view of Kim et al. (KR2017/0113961, filed 3/30/2016, published 10/13/2017, prior art of record), Scholz (US2022/0193129, filed 4/27/2018, published 6/23/2022) and Scholz (WO2016/100932, published 6/23/2016, prior art of record)
Moriarity et al. teaches methods for producing engineered primary human B cells, wherein one or more endogenous genes are deleted, and one or more exogenous genes are overexpressed (Abstract, Summary of the Invention [0006-0012], Illustrative Embodiments of Methods of Editing a Genome of a Primary B cell, [0113]).
In regard to claim 1, step (a), Moriarity teaches the stimulation and expansion of naïve-like human B cells obtained from PBMCs with exposure to the cytokines CD40L and IL-4 prior to electroporation or transfection [0039, 0070-0077].
In regard to claim 1, step (c1), Moriarity teaches delivering to the stimulated and expanded human B cells an effective amount of Cas9 and gRNAs to disrupt expression of one or more genes such as an endogenous BCR ([0081], see also Example 2, [0139-0140] targeting the BCR co-receptor CD19).
In regard to claim 1, step (d1), Moriarity teaches transducing the B cells with a vector encoding a heterologous antigen receptor, such as a heterologous BCR [0012, 0080-0082, 0137].
However, in regard to claim 1, step (b), although Moriarity teaches that B cells can be stimulated and expanded with CD40L [0069, 0072], Moriarity et al. are silent to transducing the stimulated human B cells of step (a) with a CD40 ligand (CD40L).
Kim et al. teaches methods for producing engineered B cells (Abstract and Description of Embodiments sections of translation). In regard to claim 1 step (b), Kim teaches stimulating B cells for a first time, and then transducing the stimulated B cells with CD40L (Example 1, Preparation of Recombinant B Cells, 4th para.). In regard to human B cells, although Kim reduces to practice optimal in vitro conditions for transducing recombinant lentiviruses encoding CD40L in mouse B cells, they do teach that human CD40L gene can be used.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to practice the method of producing engineered human B cells as taught by Moriarity, and combine the step (b) of transducing the stimulated B cells with a human CD40L as suggested by Kim with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so not only to have sustained expression of CD40L on the transduced human B cells to promote expansion, but also because Kim indicates the overexpression of CD40L in human B cells may prevent impulsive cell death (Example 4, Evaluation of the viability of recombinant B cells). Thus, combining step (b) in the method provides the B cells with enhanced proliferation and inhibited apoptosis through the remaining gene modification procedures, thereby achieving a proliferative and survival advantage in vitro. Note that B cell viability during gene modification in vitro is of the utmost concern to Moriarity, and he goes to great lengths to optimize the gene modification procedures to minimize cell death (e.g., see Fig. 7). Accordingly, the modified CD40L+ B cells would be a welcome addition to methods of Moriarity.
However, in regard to claim 1, step (b), although Moriarity teaches that B cells can be stimulated and expanded with CD40L, as well as IL-21 [0069, 0072], Moriarity and Kim are silent to culturing the CD40L transduced human B cells of step (b) with IL-21.
Scholz (US2022) teaches a method of producing engineered primary human B cells , comprising transducing human B cells and numerically expanding the transduced human B cells in the presence of CD40L and IL-21 ([0019], see Fig.3). Scholz (US2022) further incorporates Scholz (WO2016) by reference [0098], which teaches that after expansion in CD40L and IL-21 that human B cells can be transduced (see claims 1-12 of Scholz (WO2016).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to practice the method of producing engineered B cells transduced with CD40L as suggested by Moriarity in view of Kim, and combine the expansion step (b) with the presence of IL-21 as taught by Schloz (US2022) and Scholz (WO2016) with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Scholz (US2022) because the combination of CD40L and IL-21 induce a “large scale expansion” of the genetically modified B cells by more than 10 fold (see Fig. 3). Furthermore, Scholz (WO2016) demonstrates that expansion of human primary B cells with CD40L and IL-21 is multi-fold higher than with CD40L alone (p.63-64, Examples 7 & 8)
Note in regard to the order of steps (a), (b), (c1), and (d1), as stated supra, Moriarity teaches that stimulated and expanded B cells are more efficiently modified, thus it would have been obvious to have the stimulation and expansion step before each transduction/transfection step. Furthermore, the initial expansion of the B cells provides sufficient numbers of cells for subsequent modification steps. Thus, the method of Moriarity would start with the expansion step (a). Next, as stated supra, step (b) transduction with human CD40L as suggested by Kim would allow sustained CD40L expression for proliferation and possibly protect the human B cells during subsequent steps. Furthermore, as stated supra, it would have been obvious to include another expansion step in (b) with IL-21 as taught by Scholz et al. so as to generate sufficient cell numbers and improve the subsequent transfection/transduction steps of (c1) and (d1). In regard to gene disruption step (c1) before the transduction step (d1), Moriarity teaches that it is desirable to inactivate the endogenous BCR gene first so as to not interfere with the functionality of the exogenous BCR transgene [0081]. Thus, it would have been obvious to have the endogenous BCR gene disruption of step (c1) before the transduction of the vector encoding the heterologous BCR of step (d1). Accordingly, Moriarity in view of Kim and Scholz et al. make obvious steps (a), (b), (c1) and (d1) in that order.
In regard to claim 2, as stated supra, Moriarity teaches CRISPR Cas9 disruption of an endogenous BCR gene (step (c1)), before transducing the B cells with a vector encoding a heterologous BCR (step (d1)) so as not to interfere with the functionality of the heterologous BCR.
In regard to claim 10, as stated supra, Scholz et al. teaches the expansion in step (b) in with IL-21.
In regard to claims 12 and 13, as stated supra, Moriarity teaches electroporation of the B cell to deliver the Cas9 and gRNA, wherein 1x10^6 cells are used [0129].
In regard to claim 18, Moriarity teaches that the expansion of the primary human B cells is in the presence of IL-4 [0039, 0069, 0077, 0128].
In regard to claim 20, although Moriarity teaches the heterologous BCR comprises heavy chain and light chain genes targeting specific antigens [0137], they are silent to a heterologous BCR that is a chimeric antigen receptor.
Nevertheless, as stated supra, Scholz (WO2016) teaches methods for engineering B cells with one or more transgenes (Abstract, Summary of the Invention). Specifically, Scholz (WO2016) teaches the genetically modified B cells comprise a chimeric antigen receptor that is a fusion protein of a scFv and an intracellular signaling portion of a B cell receptor (e.g., CD40) (p. 17, 1st para.).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to have practice the method of producing engineered B cells with a heterologous BCR as taught by Moriarity, and to substituted a heterologous CAR as taught by Scholz (WO2016) with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Scholz (WO2016) because the CAR would intrinsically induce a cell signaling pathway in the B cell upon binding to its specific ligand (p. 17, 1st para.).
In regard to claim 21, Moriarity teaches the B cells are transduced with an immunoglobulin gene ([0036], Fig. 6)
In regard to claim 24, Moriarity teaches that CRISPR Cas gene editing of the B cells includes disruption of an inhibitory gene such as PD1 ([0032, 0057, 0066], see Fig. 2).
In regard to claim 26, as stated supra, Moriarity and Scholz et al. teaches the expansion of B cells is in the presence of IL-4 and IL-21. Furthermore, Moriarity teaches the gene-edited primary B cell exhibits increased capacity to expand relative to a non-genome edited primary B cell [0060]. Moreover, a final expansion step of the engineered B cells provides sufficient numbers of cells for subsequent administration steps [0101-0109]. Thus, Moriarity suggest an expansion step comprising IL-4 and IL-21 following the method step.
In regard to claim 34, as stated supra, Moriarity and Scholz et al. teaches the use of human B cells.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 11/17/2025 are acknowledged.
First, Applicant argues that the cited prior art does not teach nor suggest transducing human B cells with IL-21 or expanding transduced human B cells in IL-21. Applicant argues that the inclusion of IL-21 produced surprising effects on the expansion of CD40L transduced B cells with expanded cells increasing from 15 million cells without IL-21 to 65-100 million cells with IL-21.
Furthermore, Applicant argues that the inclusion of IL-21 surprisingly promoted a regulatory phenotype in the human B cells, which suppressed TNF-alpha, IFN-gamma, and IL-2 production in co-cultured T cells.
Finally, Applicant argues that the cited prior art of Kim directed to transducing stimulated B cells with a CD40L are in mouse B cells, not human B cells, and does not provide a reasonable expectation of success for predicting the effects of CD40L expression in human B cells. Specifically, Applicant argues that CD40L transduction in the mouse B cells of Kim increases expression of IFN-g, TNF-a, and IL-2 (Fig. 2C of Kim), while Applicant demonstrates that CD40L transduction in human B cells reduces expression of IFN-g, TNFa, and IL2 (Figs. 2D-E of disclosure).
Furthermore, Applicant argues that Moriarity acknowledges that human B cell engineering is difficult and delivering DNA to B cells can be toxic or lead to dysregulation, while Cotta-Ramusion discloses the modification of more than hundred cell types.
Applicant's arguments have been fully considered but they are not persuasive.
In response to Applicant's first arguments, a 35 U.S.C. § 103(a) based test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In instant case Moriarity teaches expansion of human B cells with CD40L and IL-4, and suggests IL-21, while Scholz et al. demonstrates that in the presence of IL-21 the expansion of human B cells is increased from about 200 fold to nearly a 1000 fold (Fig. 12 of Scholz WO2016) in the case of human memory B cells, and from about 10-100 fold to about 225-375 fold in human pan B cells (Fig. 13 of Scholz WO2016). Thus, there was good reason to include IL-21 in the human B cell expansion culture, and it was not surprising that IL-21 resulted in a significant increase in human B cell expansion.
In response to the predictability of CD40L in human B cells based on the mouse B cells of Kim, as a first matter, Moriarity acknowledges that CD40L can stimulated and expand human B cells [0069, 0072, 0077, 0128]. Thus, there was some predictability in regard to the stimulatory and expansion effects of CD40L on human B cells. As a [AltContent: textbox ([img-media_image1.png])]second matter, contrary to Applicant’s assertion, it is clear from Fig.2C of Kim that the only cytokine in CD40L transduced mouse B cells that significantly increases expression over GFP controls is IL-2 (see adjacent comparing columns 2 vs 3). It must be noted that in Applicant’s results (which measure T cell cytokines, not the B cell cytokines of Kim), there is also a significant increase in IL-2 expression (see Fig. 2D, with IL-2 Fig. 2E, Day 9 of disclosure) and trends towards increased IL-2 expression elsewhere. As a third matter, there are references of record that qualify as prior art that demonstrate that certain combinations of cytokines that included CD40L could influence the regulatory phenotype of human B cells (Example 2 of Rezvani et al., WO2018/23700, published 12/27/2018, in IDS filed 7/22/2022), thereby establishing that this is not a surprising feature of B cells exposed to CD40L. As a final matter, even if Applicant’s demonstration that certain combination of cytokines comprising CD40L and IL-21 can skew the B cells towards a regulatory phenotype is surprising, a method of producing regulatory B cells is not claimed, nor is it germane to the use of the same cytokines by the prior art to stimulate and expand B cells. MPEP 2144 (IV) states that the reason or motivation to modify a reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by Applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006). In instant case, the prior art teaches to …. The fact that Applicant has recognized another regulatory property which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Finally, in regard to Applicant’s arguments directed to the general lack of predictability in modifying human B cells, Moriarity clearly reduces to practice the stimulation and transfection with CRISPR Cas9 for gene editing of human B cells (Examples 1 & 2). Furthermore, Scholz et al. reduce to practice the stimulation and transduction of human B cells that behave in a predictable manner (Fig. 3 of Scholz US2022 and Examples 1-5, and 7-8 of Scholz WO2016). It would have been predictably obvious to stimulate, transduce and expand, gene edit, and transduce again human B cells when practicing a in vitro method of Moriarity et al. In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988) (citations omitted) (The court held the claimed method would have been obvious over the prior art relied upon because one reference contained a detailed enabling methodology, a suggestion to modify the prior art to produce the claimed invention, and evidence suggesting the modification would be successful.). Therefore, one of ordinary skill in the art could have pursued the known potential option of combining the steps of (a) – (d) in human B cells with a reasonable expectation of success. This reasonable expectation of success is supported by: (1) the references of Moriarity and Scholz et al. contained detailed enabling methodologies for the stimulation, gene editing, expansion and transduction of human B cell that could have easily been applied in different orders in vitro to huma B cells, (2) Kim provides a suggestion to apply the taught method to also include transduction of CD40L, and (3) the success of stimulating, gene editing, expansion and transduction of human B cells as taught by Moriarity and Scholz et al. suggest modification of the method to include other transgenes (to wit, CD40L) would have been successful.
Applicant is reminded that any conclusions of unpredictability have to be made in the context of this particular in vitro method, which does not exclude any cytokines from being used nor require a particular efficiency or property of the modified human B cells. Furthermore, the Federal Circuit would have found that the claims at issue would have been obvious since there had been ample suggestion in the prior art that the claimed method to produce transduced and gene edited human B cells would have worked. Absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. The Federal Circuit concluded that Applicant’s “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304.
Claims 4-6 are rejected under 35 U.S.C. 103 as being unpatentable over Moriarity et al. (US2022/0168342, filed 9/12/2017, published 6/02/2022, prior art of record), in view of Kim et al. (KR2017/0113961, filed 3/30/2016, published 10/13/2017, prior art of record), Scholz (US2022/0193129, filed 4/27/2018, published 6/23/2022) and Scholz (WO2016/100932, published 6/23/2016, prior art of record), as applied to claims 1 and 24, in further view of Cotta-Ramusino et al., (US 12,359,223, filed 1/30/2019, patented 7/15/2025)
As discussed previously, Moriarity in view of Kim and Scholz et al. suggest teaches methods of producing engineered CD40L+ B cells comprising disruption in one or more genes and a heterologous BCR.
In regard to claims 4-6, although Moriairty teaches that more than one gene is to be disrupted, such as the endogenous BCR and the inhibitory gene PD1, they are silent to the method steps wherein the gRNA targeting the first gene (e.g., BCR) are delivered in a first step, and then the gRNAs targeting the second gene (e.g., PD1) are delivered in a second step, and the first and second delivery steps are separated by at least about 2 days.
In regard to claims 4 and 5, Cotta-Ramusino teaches the sequential modification of immune cells, including B cells, comprising first delivery step comprising delivering a first gRNA that targets one gene, waiting a period of time sufficient for repair of the first cleavage site, followed by a second delivery step comprising delivering a second guide RNA that targets a different gene (col 3, col 10, col 26, last para., col 88, lines 12-14, col 112-113, see Example 3). In regard to claim 6, Cotta-Ramusino teaches the period of time is at least about 48 hours (col 3, lines 55-56, col 10, line 29, Claims 6 and 9 of Cotto-Ramusino, see also Example 3)
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to have practice the method of producing engineered B cells with two CRISPR Cas9 mediated gene disruptions as taught by Moriarity, and to have performed the two gene disruptions by two delivery steps, where there was at least about 2 days after the first delivery step as taught by Cotta-Ramusino with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so for several reasons. First, the genus of options for generating a double modified cells are either sequential or parallel. Since the size of this genus is so small, one of ordinary skill in the art would have immediately envisioned the sequential option. Furthermore, Cotta-Ramusino teaches at least about a 2 day waiting period after CRISPR modification of cells in order to allow repair of the first cleavage site. Importantly, Cotta-Ramusino teaches that this reduces the reduces the risk of unwanted translocation events (Summary, col 2, Example 3, col 113, see Fig. 8).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 11/17/2025 are acknowledged.
Claims 16 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Moriarity et al. (US2022/0168342, filed 9/12/2017, published 6/02/2022, prior art of record), in view of Kim et al. (KR2017/0113961, filed 3/30/2016, published 10/13/2017, prior art of record), Scholz (US2022/0193129, filed 4/27/2018, published 6/23/2022) and Scholz (WO2016/100932, published 6/23/2016, prior art of record), as applied to claims 1 and 18, in further view of Johnson et al., (Sci Reports, 2018, 8:12144, pgs. 3-9, prior art of record)
As discussed previously, Moriarity in view of Kim and Schloz et al suggest teaches methods of producing engineered CD40L+ B cells comprising expanding the B cells in IL-4 and IL-21, disruption in one or more genes by CRISPR Cas9 and transduction by a heterologous BCR.
In regard to claim 16, although Moriarity teaches the delivery of the gRNA by an electroporation step, they are silent to using a 3 micromolar concentration of gRNA.
Nevertheless, Moriarity had published a detailed method for engineering B cells with the co-inventor Johnson in Johnson et al. (2018). Johnson teaches 1 microgram of sgRNA in 10 microliters of buffer for electroporation of the B cells (p. 2, Materials and Methods, 3rd para.). Since single guide RNAs are about 100 nucleotides in length, and each RNA nucleotide is about 320 g/mol, a 0.1 g/L solution of sgRNA is at a concentration of a about .0000031 mol/l (i.e., 3.1 micromolar).
In regard to claim 19, although Moriarity teaches the stimulation and expansion of B cells in the presence of the cytokine IL-4, they are silent to using 100 units/ml of IL-4.
Nevertheless, Moriarity had published a detailed method for engineering B cells with the co-inventor Johnson in Johnson et al. (2018). Johnson teaches 125 units/ml of IL-4 for the expansion of B cells (p. 2, Materials and Methods, 2nd para.).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to have practice the method of producing engineered CD40L+ B comprising the steps of electroporation of B cells with gRNAs and/or the expansion of B cells in IL-4 as taught by Moriarity et al., and to have performed the electroporation of B cells with 3.1 micromolar sgRNA, and/or the expansion of B cells in 125 units/ml of IL-4 as taught by Johnson with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so for several reasons. First, Johnson and Moriarity are co-inventors and co-authors of Johnson et al., and the patent document of Moriarity shares figures with the non-patent literature of Johnson (e.g., Fig. 9 vs Fig. 2, respectively). Thus, one of ordinary skill in the art would have sought out related disclosures by the same inventors for guidance in the modification of the patent’s methods such as choose about 3.1 micromolar sgRNA during electroporation and 125 units/ml IL-4 in the expansion step. This would have been recognized as simply combining related prior art amounts according to known methods to yield predictable results. Furthermore, in regard to the amounts disclosed by Johnson, MPEP 2144.05(I) states that a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). See also In re Brandt, 886 F.3d 1171, 1177, 126 USPQ2d 1079, 1082 (Fed. Cir. 2018)(the court found a prima facie case of obviousness had been made in a predictable art wherein the claimed range of "less than 6 pounds per cubic feet" and the prior art range of "between 6 lbs./ft3 and 25 lbs./ft3" were so mathematically close that the difference between the claimed ranges was virtually negligible absent any showing of unexpected results or criticality.).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 11/17/2025 are acknowledged.
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
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/ARTHUR S LEONARD/Examiner, Art Unit 1631