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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 5, 2026, has been entered.
DETAILED ACTION
The amended claims filed on March 5, 2026, have been acknowledged. Claims 4-5, 7-8, 10-15, 19, 21, 23, and 25-36 were cancelled. Claims 1-3, 6, 9, 20, 22, 24, 37-38, and 41 were amended. Claims 1-3, 6, 9, 16-18, 20, 22, 24, and 37-45 are pending and examined on the merits.
Priority
The applicant claims domestic priority from U.S. provisional application No. 62/750,603, filed on October 25, 2018. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1-3, 6, 9, 16-18, 20, 22, 24, and 37-45 receive domestic benefit from U.S. provisional application No. 62/750,603, filed on October 25, 2018.
Information Disclosure Statement
The information disclosure statement (IDS) filed on March 5, 2026, has been considered.
Withdrawn Claim Rejections - 35 USC § 102
The prior rejection of claims 1-3, 6, 16-18, 20, 22, 24, 37-38, 40-41, and 43-45 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by World Intellectual Property Organization Patent Application No. 2018106732 (Beauchesne; designated US; identified in IDS), as evidenced by Klebanoff et al. (J Clin Invest. 126:318-334. 2016; identified in IDS), Crompton et al. (Immunol Rev. 257: 264–276. 2014), and Setoguchi et al. (International Immunology 28: 293–305. 2016) is withdrawn in light of Applicant’s amendment to claim 1 to recite that the transducing step comprises deoxynucleosides.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2, 16, and 44-45 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 recites that “the population of immune cells is not expanded, or is expanded by no more than,”. It appears that the level of expansion for comparison is missing. For example, subclaims (b) and (c) of claim 2 use similar language but include a percentage change of 30%. Applicant is recommended to amend to include the relevant percentage change or any other appropriate, similar language to subclaim (a).
Claims 16 and 44-45 are also rejected because of their dependence on claim 2.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1-3, 6, 9, 16-18, 20, 22, 24, and 37-45 are rejected under 35 U.S.C. 103 as being unpatentable over World Intellectual Property Organization Patent Application No. 2018106732 (Beauchesne; designated US; identified in IDS) and Plesa et al. (Journal of Virology 81: 13938–13942. 2007; identified in IDS), as evidenced by Klebanoff et al. (J Clin Invest. 126:318-334. 2016; identified in IDS) and Setoguchi et al. (International Immunology 28: 293–305. 2016). This is a new rejection made in response to Applicant’s amendments to claim 1. Any aspect of Applicant’s traversal that is relevant to the rejection as newly written is addressed below.
Regarding claims 1, 9, and 39, Beauchesne teaches a method of transducing resting T cells with a CAR comprising: Autologous peripheral blood mononuclear cells (PBMCs) were collected from a patient using a leukapheresis collection system. Cells of the leukapheresis sample were washed and resuspended in a buffer for use in affinity-based selection, the buffer containing Phosphate Buffered Saline (PBS), EDTA and human serum albumin;
Beauchesne teaches that their method can include an additional incubation step prior to the enriching and/or selecting cells, cells from a sample are transferred or suspended in a serum-free media. This incubation step can occur for up to 12 hours;
For immunoaffinity-based selection of T cells, the washed cells in the selection buffer were incubated for 30 minutes at room temperature with magnetic beads CD4 and CD8 T cells were enriched by immunoaffinity-based selection using magnetic beads coupled to monoclonal antibodies, which were added to the washed leukapheresis within the centrifugal chamber. Beads were mixed in the selection buffer described which then was sterilely connected to the apparatus. A program was run on the Sepax® 2 unit which caused the bead mixture and selection buffer to be drawn into the chamber with the washed cells, and the contents of the chamber to be mixed for 30 minutes (i.e. an incubation step without serum);
Isolated CD4 and CD8 T cells were transduced with a lentiviral vector containing a nucleic acid encoding a transgene (a chimeric antigen receptor (CAR) and a truncated EGFR) without prior activation. A transduction reagent solution was prepared containing complete media (X-VIVO-15 containing 5% (v/v) human serum, 1.6 mg/mL N-Acetylcysteine (NAC) and 100 IU/mL IL-2) and a polycation in an amount sufficient for a final concentration during transduction initiation of 10 μg/mL), viral vector particles (approximately 3.2 IU/cell), and, where applicable, air. The transduction reagent solution was aseptically transferred to a centrifuge bag comprising approximately 2 x 108 selected CD4/CD8 T cells. To initiate transduction, the virus and cells were spun in the cavity of the chamber at an approximate RCF at the internal wall of the cavity of 1600 g. The spin was carried out at the indicated speed for 1 hour. The transduced material was then transferred into an output bag (i.e. the cells express the CAR) (Examples 1 and 2 and paragraphs 0118-0119).
Beauchesne teaches that their lentiviruses can be HIV based lentiviruses (paragraph 0335 and page 159, embodiment 45).
Beauchesne does not teach wherein deoxynucleosides are added to the media for transduction.
However, Plesa teaches that deoxynucleoside (dN) addition enhanced HIV (HIV viruses are a type of lentivirus) integration in resting CD4+ T cells (abstract). They find that dN enhancement of integration occurs at 50 μM (page 13939, column 1, paragraph 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the transduction method of Beauchesne to culture the CD4/CD8 T cells with 50 μM deoxynucleosides to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Plesa teaches that deoxynucleosides enhanced HIV integration in resting CD4+ T cells at 50 μM. As such, it would have been obvious to include the deoxynucleosides to improve the transduction efficiency to increase the number of CAR expressing cells. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 2, Beauchesne teaches that the engineered cells can be administered immediately or shortly after transduction without ex vivo expansion, including administering the engineered cells immediately after the transduction step (paragraphs 378-380).
Regarding claim 3, as stated supra, Beauchesne teaches that their method can include an additional incubation step prior to the enriching and/or selecting cells, cells from a sample are transferred or suspended in a serum-free media. This incubation step can occur for up to 12 hours (paragraphs 0118-0119).
Regarding claim 6, as stated supra, Beauchesne teaches that they used 5% human serum in their lentiviral transduction media (Examples 1 and 2).
Regarding claim 16, Klebanoff evidences that adoptive cell transfer (ACT) of purified naive, stem cell memory, and central memory T cell subsets results in superior persistence and antitumor immunity compared with ACT of populations containing more-differentiated effector memory and effector T cells. ACT methods using genetically modified T cells or TILs rely on ex vivo expansion of cells to large numbers which invariably drives cells toward terminal differentiation (abstract and page 9, paragraph 1). As such, the method of Beauchesne wherein the cells are administered soon after transduction would have a more naïve state than if the cells were expanded for 6 days and would have an increased persistence as a result.
Regarding claim 17, Beauchesne teaches that the CAR can include an extracellular binding domain (such as an antigen binding domain), a transmembrane domain, and an intracellular signaling domain (paragraphs 0214 and 0265).
Regarding claim 18, Beauchesne teaches that the antigen binding domain binds to CD19 (paragraphs 0218 and 0265).
Regarding claim 20, Beauchesne teaches that the transmembrane domain is from CD28 (paragraphs 0239 and 0265).
Regarding claim 22, Beauchesne teaches that the CAR can comprise a primary cytoplasmic signaling domain (paragraphs 0245 and 0265).
Regarding claims 24 and 38, Beauchesne teaches that the CAR can comprise an intracellular signaling domain containing a signaling portion of 4-lBB and a signaling portion of CD3 zeta signaling domain (paragraph 0265).
Regarding claim 37, Beauchesne teaches a hinge region set forth in SEQ ID NO: 30 that has 100% sequence identity to SEQ ID NO: 3 of the instant application (paragraph 0264).
Regarding claim 40, as stated supra, Beauchesne teaches that their method can include an additional incubation step prior to the enriching and/or selecting cells, cells from a sample are transferred or suspended in a serum-free media. This incubation step can occur for up to 12 hours (paragraphs 0118-0119).
Regarding claim 41, as stated supra, Beauchesne teaches that their method can include an additional incubation step prior to the enriching and/or selecting cells, cells from a sample are transferred or suspended in a serum-free media. This incubation step can occur for up to 12 hours which is at least 2-6 hours (paragraphs 0118-0119).
Regarding claim 42, Beauchesne teaches that they used a lentivirus for transduction and that cells could be transduced in the well of a plate instead of as part of the Sepax 2 system. This transduction involved administering the transduction media with the lentivirus to the CD4/CD8 T cells in a well of a plate, centrifuging for 1 hour, and incubating for 24 hours (Examples 1 and 2). The approximately 25 hours is considered to fall within the about 24 hours of claim 42 based on Applicant’s definition of about (±20%). As stated supra, Plesa provides justification for adding deoxynucelosides into the transduction media at 50 μM to enhance integration of the transgene.
Regarding claim 43, Beauchesne teaches that the concentration of input cells for transduction can be 1 x 107 cells/mL (paragraph 0356).
Regarding claim 44, as stated supra, Beauchesne teaches that the engineered cells can be administered immediately after transduction (paragraphs 378-380). As such, the transduced cells of Beauchesne can be administered to a patient without expansion.
Regarding claims 2 and 44-45, Beauchesne teaches that terminally differentiated effector memory T cells can be used in their transduction method (paragraphs 0108-0109). As Beauchesne teaches that the cells can include just the subpopulation of terminally differentiated effector memory T cells, the percentage of these cells in the population cannot increase above 100% (the starting percentage). Setoguch evidences that terminally differentiated effector memory T cells are CCR7low (abstract).
Response to Arguments
Applicant's arguments filed March 5, 2026, are acknowledged.
Applicant argues that the art cited by the Examiner, considered separately or together, do not teach all elements of the claims. For instance, Beauchesne, which the Office relies on as allegedly teaching the serum-free incubation step (Office Action at page 5), in fact does not teach or even suggest a step of incubating a population of immune cells in a medium that does not comprise serum. Beauchesne is directed overall to methods for genetically engineering cells in which the sample of cells taken from the subject prior to use in the method and the input population comprises serum and/or has been contacted with serum ex vivo (see, e.g., Beauchesne at least paragraphs [0018], [0019], [0022], [0023], [0064], [0347], and claims 22-25, 30, and 32).
Beauchesne specifically states in some of any such embodiments, the sample contains serum or plasma at a concentration of at least or at least about 30% (vlv); and/or prior to the incubating, the sample has been contacted ex vivo with serum or plasma at a concentration of at least or at least about 30% (vlv). In some aspects, the serum or plasma is human. In some cases, the serum or plasma is autologous to the subject (Id at [0019]).
The Office alleges that paragraphs [0118]-[0119] teach "an additional incubation step prior to the enriching and/or selecting cells, cells from a sample are transferred or suspended in a serum-free media. This incubation step can occur for up to 12 hours" (Office Action at page 9). This is an incorrect interpretation of the text. Paragraph [0118] and [0119] are isolated passages describing two different options for steps that can be performed prior to enriching or selecting the cells in the method of Beauchesne, and thus paragraph [0119] does not provide any time limits for the duration of what is recited in paragraph [0118]. Paragraph [0119] recites that the method can comprise a resting step further to prior to the selection and/or enrichment of cells and that the sample can be maintained or held at a particular temperature for up to 12 hours. This timing therefore merely relates to the time at which the cells are incubated at a specific temperature prior to the method. Nowhere in paragraph [0119] or in Beauchesne does it recite incubating in serum free media for any particular period of time, let alone for at least 1 hour.
Like paragraphs [0118] and [0119], paragraph [0117] of Beauchesne provides another option of a step that can be performed prior to enriching or selecting the cells, which is the opposite of paragraph [0118], in that it teaches that the sample is to be contacted with or contain human serum. This is further evidence of the independence of these three paragraphs. Therefore, one of skill in the art reading paragraphs [01 l 7]-[0119] would understand these paragraphs simply present three different steps that can be performed prior to enriching or selecting cells in the methods of Beauchesne. Beauchesne does not teach incubating a population of immune cells in a medium that does not comprise serum, or comprises no more than 2% serum, for at least 1 hour. The only timing Beauchesne teaches in the passages cited by the Office is for incubation at a particular temperature, not in particular media.
To the extent that Beauchesne recites incubation in serum free media, Beauchesne provides absolutely no guidance as to how long to incubate the cells in serum-free media or to even combine incubating a population of immune cells in a medium that does not comprise serum, or comprises no more than 2% serum, for at least 1 hour in combination with transducing the population of immune cells with a nucleic acid molecule encoding the CAR, in a medium comprising deoxynucleosides, let alone that such a combination would be successful. Accordingly, one of skill in the art starting with Beauchesne, would not have been motivated to modify the teachings of Beauchesne to arrive at the presently claimed method and in fact would have followed the method of Beauchesne which overwhelmingly describes an input population comprising serum or being contacted with serum ex vivo (page 10, paragraph 6-page 13, paragraph 1).
Applicant's arguments have been fully considered but they are not persuasive.
The MPEP 2123 (I) states that patents are relevant as prior art for all they contain, and that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Furthermore, MPEP 2143.01(I) states that the court stated that "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." Id. In affirming the Board’s obviousness rejection, the court held that the prior art as a whole suggested the desirability of the combination of shoe sole limitations claimed, thus providing a motivation to combine, which need not be supported by a finding that the prior art suggested that the combination claimed by the applicant was the preferred, or most desirable combination over the other alternatives. Id. See also In re Urbanski, 809 F.3d 1237, 1244, 117 USPQ2d 1499, 1504 (Fed. Cir. 2016).
In the instant case, although Beauchesne identifies that prior to enriching or selecting the cells, the cells can be incubated with human serum (paragraph 0117 as identified by the Applicant), Beauchesne specifically teaches that their method can include an additional incubation step prior to the enriching and/or selecting cells, cells from a sample are transferred or suspended in a serum-free media (paragraph 0118). At no point does Beauchesne teach away from using serum-free media.
Therefore, Beauchesne positively identifies a method of making immune cells that express a CAR comprising incubating a population of immune cells in a medium that does not comprise serum.
Regarding the timing of the incubation, as identified by the Applicant, paragraph 0119 of Beauchesne does not recite a specific media composition for the timing of the incubation. There is nothing within paragraph 0119 that would exclude serum-free media from the timing component. Paragraphs 0118-0119 are specifically related to the step prior to the selection and/or enrichment of cells. Therefore, one of ordinary skill in the art would understand that the timing of the incubation prior to the selection and/or enrichment of cells can be used with the recited media of paragraph 0118.
Therefore, Beauchesne does teach incubating the immune cells in a medium without serum for at least 1 hour.
Applicant argues that their method provides unexpected results in improving CAR T cell manufacturing and transduction efficiency in T cells that could not have been predicted or expected from Beauchesne or Plesa, alone or in combination (see, e.g., Examples 1 and 4 and Figures 2B and 6B). It was evaluated whether a brief serum starvation prior to lentiviral vector transduction would increase lentiviral vector transduction of quiescent T cells. As shown in FIG. 2A, as little as 2 hours of serum starvation increases the transduction of quiescent T cells with about 10-fold increase achieved after 6 hours (Application as filed at page 133 at lines 21-25). As shown in FIG. 2B, supplementation of the culture medium with deoxynucleosides (dNs), which enhance reverse transcription, at a 50 μM concentration increases transduction efficiency of quiescent T cells by 3-fold compared with cells maintained in medium containing IL-7 and IL-15. Combining both serum starvation and high concentrations of dNs permits transduction efficiencies exceeding 50% in quiescent T cells (FIG. 2B) (Id. at page 133, lines 27-32; emphasis added) (page 13, paragraph 3-page 14, paragraph 2).
Applicant's arguments have been fully considered but they are not persuasive.
Although Applicant argues unexpected results, the claims are not commensurate in scope with the experimental results cited by the Applicant. MPEP 716.02(d) discloses that whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. See In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.).
Regarding the claims at issue in the instant application, claim 1 encompasses performing their method with incubation of the immune cells in serum free media for at least 1 hour while Examples 1 and 4 performed their serum starvations for 2-6 hours or 3 hours, respectively. Furthermore, during the transduction step, claim 1 encompasses any amount of serum in the medium and any length of time for incubation while the cited examples incubate the immune cells in a medium comprising 5% serum with 50μM deoxynucleosides, IL-7, and IL-15 in X-VIVO 15 media for 20 hours.
As such, the claims as written are not commensurate in scope with alleged unexpected results.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEENAN A BATES whose telephone number is (571)270-0727. The examiner can normally be reached M-F 7:30-5:00.
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/KEENAN A BATES/Examiner, Art Unit 1631
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