DETAILED ACTION
This action is in reply to papers filed 07/07/2026.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 99, 104, and 113-130 are pending and examined on the merits herein.
Claims 128-130 are new.
No previously presented claims have been amended.
Election/Restrictions
Applicant previously elected without traverse Group II, drawn to claims 99, 104, and 113-127, in the reply filed on 01/29/2026.
Status of Objections/Rejections
The objection to the disclosure regarding the mislabeling of tables is withdrawn in light of the amendment to the specification.
Maintained rejections are set forth below. Applicant’s arguments are addressed following the maintained rejections.
Claim Interpretation
Claims 124, 126, and 130 are product-by-process claims. Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. See MPEP 2113. In the instant case, the method steps of claims 123 or 99 do not clearly impart additional structural limitations to the products of claims 124 and 126, respectively. Therefore, claims 124 and 126 are interpreted as “a population of primary B cells transduced with a lentiviral vector.” Likewise, claim 130 is interpreted as “a population of human naïve B cells transduced with a lentiviral vector.”
The phrase “pharmaceutical composition comprising the population of cells” (claims 125 and 127) is not defined in the specification. Therefore, the broadest reasonable interpretation of this phrase, which includes a composition comprising the population of cells in saline, PBS, or culture medium, is used for the purposes of examination.
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.
Claim(s) 99, 104, 113, and 126-127 remain rejected under 35 U.S.C. 103 as being unpatentable over Gong (Molecular Therapy Methods & Clinical Development, 2020, 17: 634-646; cited in IDS 07/28/2023), in view of Janssens (Human Gene Therapy, 2003, 14(3): 263-276).
Regarding claims 99 and 126-127: Gong teaches a method of transducing NK cells by contacting the cells with statins and a lentiviral vector (Abstract). Gong teaches that low-density lipoprotein-receptor (LDLR), the receptor of vesicular stomatitis virus (VSV), is expressed at low levels on NK cells. Gong teaches that transduction efficiency of NK cells with VSV-G pseudotyped lentivirus is augmented by statins that induce higher low-density lipoprotein-receptor (LDLR) expression (Abstract). Gong teaches that in both NK-92 cells and primary NK cells, the transduction efficiency increased after treatment with statins that induce higher LDLR expression, especially with rosuvastatin (Abstract).
Gong teaches that the LDLR expression levels in human B and T lymphocytes can be influenced using compounds compatible with in vitro culture, including statins (Results, para 1).
The method of Gong comprises transduction of NK cells. Gong does not teach a method of transducing primary B cells.
Janssens teaches that human primary B cells can be transduced by VSV-G pseudotyped lentiviral vectors (Abstract). Janssens teaches that gene transfer into primary B cells is a promising strategy to cure genetic diseases associated with B-cell dysfunction, and that long-lasting transgene expression in B cells is of particular interest for immunotherapy for its potential to induce specific immune activation or tolerance (p 263, col 1).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the invention to have modified the method of Gong by transducing primary B cells instead of NK cells. One of ordinary skill in the art would have been motivated to make this modification because Janssens teaches that lentiviral gene transfer into primary B cells is a promising strategy to cure genetic diseases associated with B-cell dysfunction and is of particular interest for immunotherapy. One of ordinary skill in the art would have had a reasonable expectation of making this modification because Janssens teaches that primary B cells can be transduced by VSV-G pseudotyped lentiviral vectors, and Gong teaches that LDLR expression levels in human B cells can be influenced using compounds compatible with in vitro culture (Results, para 1).
Regarding claim 104: Following the discussion of claim 99, Gong teaches the use of rosuvastatin at a final concentration of 20 μM, 5 μM, and 0.5 μM (Materials and Methods, “Co-culture of NK Cells with Statins and Non-Statin Compounds”). The lentiviral vector taught in Gong is a VSV-G pseudotyped vector (Abstract). Janssens teaches isolating human CD19+ primary B cells from the mononuclear cell population of donor blood (reads on human naïve B cells) (p 265, col 1, para 3 – col 2, para 1).
Regarding claim 113: Following the discussion of claim 99, Gong teaches the use of Atorvastatin, fluvastatin, pravastatin, rosuvastatin, and simvastatin (Materials and Methods, “Co-culture of NK Cells with Statins and Non-Statin Compounds”).
Claim(s) 99 and 114-125 remain rejected, and new claims 128-130 are rejected, under 35 U.S.C. 103 as being unpatentable over Gong (Molecular Therapy Methods & Clinical Development, 2020, 17: 634-646; cited in IDS 07/28/2023), in view of Janssens (Human Gene Therapy, 2003, 14(3): 263-276) and Su (Journal of Immunology, 2016, 197(10): 4163-4176).
Gong, in view of Janssens, renders obvious claim 99.
Regarding claims 114-115 and 118-121: Gong, in view of Janssens, does not teach co-incubating primary B cells with one or more cytokines prior to or simultaneously with the one or more statins.
Su teaches a B-cell culture system in which B-cell populations are expanded on stromal feeder cells that express low levels of CD154 (also called CD40 ligand or CD40L) (claims 118-119) in medium containing the recombinant human cytokines IL-2 (50 ng/mL), IL-4 (10 ng/mL), IL-21 (10 ng/mL), and BAFF (10 ng/mL) (Results, para 1; Materials and Methods, “CD culture system,” para 1) (claims 114-115, 120-121). Su teaches that this culture supports extensive B cell proliferation, with ∼103-fold increases following 8 days in culture and 106-fold increases when cultures are split and cultured for 8 more days (Abstract).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the invention to have modified the method of Gong, in view of Janssens, by co-incubating the primary B cells with IL-2 (50 ng/mL), IL-4 (10 ng/mL), IL-21 (10 ng/mL), and BAFF (10 ng/mL) on feeder cells that express CD40 ligand, as taught in Su. One of ordinary skill in the art would have been motivated to make this modification because Su teaches that a B-cell culture system in which B-cell populations are expanded on stromal feeder cells that express low levels of CD40 ligand in medium containing the recombinant human cytokines IL-2 (50 ng/mL), IL-4 (10 ng/mL), IL-21 (10 ng/mL), and BAFF (10 ng/mL) supports extensive B cell proliferation (Results, para 1; Materials and Methods, “CD culture system,” para 1; Abstract). One of ordinary skill in the art would have had a reasonable expectation of making this modification because Su teaches that primary B cells can be co-incubated with feeder cells and cytokines.
Regarding claims 116-117 and 122-125: Following the discussion of claim 99, Gong teaches the use of Atorvastatin, fluvastatin, pravastatin, rosuvastatin, and simvastatin (Materials and Methods, “Co-culture of NK Cells with Statins and Non-Statin Compounds”).
Regarding claim 128: Following the discussion of claims 99 and 104, Gong teaches the use of rosuvastatin at a final concentration of 20 μM, 5 μM, and 0.5 μM (Materials and Methods, “Co-culture of NK Cells with Statins and Non-Statin Compounds”).
Regarding claims 129-130: The limitations of claim 129 comprises limitations from claims 99, 104 (steps (a)-(b) of claim 129), and 120 (step (b) of claim 129). The limitations in claim 129 that correspond to the limitations in claims 99 and 104 are rendered obvious over Gong, in view of Janssen, as set forth above. The limitations in claim 129 that correspond to the limitations in claim 120 are rendered obvious over Gong, in view of Janssen and Su, as set forth above.
The product of claim 130 is rendered obvious over Gong, in view of Janssen and Su, for the same reason as claim 129.
Response to Arguments
Re: Rejections under 35 U.S.C. § 103
A. The Office Has Not Established a Prima Facie Case of Obviousness
Applicant argues: The Office has not explained why a POSA would have reasonably expected that "transduction efficiency is increased in comparison to transduction in the absence of the one or
more statins" as recited by the present claims.
Gong does not teach or suggest that "LDLR expression levels in human B cells can be
influenced using compounds compatible with in vitro culture" as the Office contends. Consistent
with Gong's focus on NK cells, the cited paragraph in Gong refers to "the human NK cell line NK-
92." Gong, page 635, col. 2, Results, para 1. Moreover, as stated in the present specification, "B
cells and primary cells are more difficult transduce than cell lines." Specification, page 26. Thus,
Gong's teachings with respect to NK cells are of limited relevance to B cells.
The Office's factually inaccurate assertion regarding the expectations of a POSA does not provide the specificity required to show unpatentability based on the proposed combination of references. Nor does the Office's assertion meet the standard for an obviousness analysis. See Unigene Labs., Inc. v. Apotex, Inc., 655 F.3d 1352, 1360 (Fed. Cir. 2011) ("Obviousness requires more than a mere showing that the prior art includes separate references covering each separate limitation in a claim under examination. Rather, obviousness requires the additional showing that a person of ordinary skill at the time of the invention would have selected and combined those prior art elements in the normal course of research and development to yield the claimed invention") ( citations omitted).
In response: Applicant’s arguments have been fully considered, but are not persuasive. First, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Gong does not teach the limitation regarding B cells, but this limitation is taught in Janssens, as set forth in the rejection.
Regarding applicant’s arguments that the Office’s assertion does not meet the standard for an obviousness analysis, the body of the rejection sets forth why a POSA would have had motivation to combine the teachings of Gong and Janssens, and moreover, why a POSA would have had a reasonable expectation of success in carrying out the modification. See page 4 of the instant Office Action and discussions regarding claims 99 and 126-127 therein.
B. Applicant's Rebuttal Evidence Establishes Non-Obviousness
Applicant argues: The claimed invention exhibits unexpected properties sufficient to rebut any arguments of obviousness.
The present specification provides data to demonstrate that the claimed method employing a statin provides unexpected benefits relative to the method in the absence of a statin. In Example 1, naive B cells were incubated without a stain or with rosuvastatin at a dose of 0.5 μM, 5 μM, or 20 μM. Following incubation, the B cells were transduced with a GFP-expressing lentiviral vector, and “It was surprisingly discovered that B cells incubated with rosuvastatin in culture with CD40L expressing feeder cells at all doses tested were transduced about 100-fold more than B cells that were not incubated with rosuvastatin (Fig. lA-C). While only about 5% of B cells were transduced without rosuvastatin, over 80% of B cells were transduced with rosuvastatin at all doses tested” (Specification, [0189] on page 23). Importantly, this increased viral transduction efficiency does not come at the expense of substantially reduced target cell activity and function. In Example 3, it is demonstrated that B cells retained antibody class switching after statin treatment. See, Specification [0199] on page 28; see also Fig. 3, which shows that addition of the statin did not alter the percent of B cells expressing the measured subclasses of antibody.
Even if the Office has established a prima facie case of obviousness (which it has not), "when an applicant demonstrates substantially improved results, as ... here, and states that the results were unexpected, this should suffice to establish unexpected results in the absence of evidence to the contrary." In re Soni, 54 F.3d 746, 751 (Fed. Cir. 1995); see also Ex parte Freeman, Appeal 2023-000512 (May 24, 2024). The Office has presented no such evidence to the contrary, only mere conclusory statements. Indeed, the Office has not provided any basis to question Applicant's statements in the specification. Thus, Applicant's presentation of data demonstrating synergy and statement that the results were surprising "should suffice to establish unexpected results." Id.
In response: Applicant’s arguments have been fully considered, but are not persuasive. Applicant’s arguments regarding unexpected results are directed toward the claimed method employing a statin relative to the method in the absence of a statin. As set forth in the rejection above, Gong teaches that the transduction efficiency of NK cells increase following treatment with statins, compared to the absence of statins.
Moreover, it is noted that the features upon which applicant relies (i.e., the fold-increase and percent increase in transduction efficiency of B cells incubated or transduced with rosuvastatin; that is, the degree of increase in transduction efficiency) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Risa Takenaka whose telephone number is (571)272-0149. The examiner can normally be reached M-F, 12-7 EST.
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/RISA TAKENAKA/ Examiner, Art Unit 1632
/KARA D JOHNSON/ Primary Examiner, Art Unit 1632
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