DETAILED ACTION
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 .
Response to Amendments
Applicant's amendments filed 6/18/2025 to claims 12-14, 18, and 30-31 have been entered. Claims 26 and 32 have been canceled. Claims 12-14, 18 and 30-31 remain pending and are being considered on their merits. References not included with this Office action can be found in a prior action. Any rejections of record not particularly addressed below are withdrawn in light of the claim amendments and applicant’s comments.
Election/Restrictions
Applicant’s election of Group III, drawn to a method of using a culture system to identify a candidate agent, and the species of “survival” in claims 12, 14 and 18, in the reply filed on 5/15/2024 stands.
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 12-14, 18, and 30-31 remain 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 12 recites the limitation in part (g), “selecting the at least one candidate agent that inhibits the CLL and lymphoma cells for the treatment of the subject, wherein the CLL or lymphoma cells are isolated from” (emphasis added). It is unclear what “wherein the CLL or lymphoma cells are isolated from” limits to as this limitation does not define where said cells are isolated from. The use of the comma after the term “subject”, and prior to the “wherein” limitation in question, appears to separate these two limitations, and therefore does not provide clarity as to where this phrase is limiting the cells being “from”. As such the metes and bounds of the claim cannot be determined. Clarification within the claim is required.
Because claims 13-14, 18 and 30-31 depend from indefinite claim 12 and do not clarify the point of confusion, they must also be rejected under 35 U.S.C. 112, second paragraph.
Response to Arguments
Applicant's arguments filed 6/18/2025 have been fully considered but they are not persuasive. Applicant alleges that the amendments to the claims overcome this rejection. However, for the reasons stated above, the amendments introduced new reasons for indefiniteness and therefore this argument is not persuasive.
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.
Claims 12-14, 18 and 30-31 remain rejected under 35 U.S.C. 103 as obvious over Hartwell et al (USPGPUB 20130338092) in view of Purroy et al (2014, Oncotarget, 6(10):7632–7643 and Slinger et al (2017, Leukemia, 31, 2601–2607).
Regarding claims 12 and 18, Hartwell teaches a method of identifying a candidate small molecule chemotherapeutic agent comprising setting up ex vivo cell culture systems comprising bone marrow stromal cells (BMSCs; MSCs and OP9) and human leukemia cells isolated from a human subject divided into separate cultures, treating each culture with either the candidate agent or a carrier (vehicle) control for a predetermined period of time, measuring and comparing the amount of apoptosis and survival of the leukemia cells wherein the identified candidate agent decreases survival of the leukemia cells as compared to a carrier (vehicle) only control, and selecting said agent for administration of said agent to the subject (see paragraphs 6-9, 167-168, 173-188, 238-234 & 241, and Examples 2-7). Regarding claim 12, Hartwell specifically teaches that this co-culture assay method allows for the selection of clinically relevant on drug for the treatment of leukemia patients in a clinic (see paragraph 239). Regarding claims 12-14, Hartwell teaches it is useful to include various factors and cytokines interleukin-3 (IL-3) and thrombopoietin (TPO) with the bone marrow stromal cells (see paragraph [0401] and Examples 2-7). Regarding claim 18, examples wherein the predetermined period of time is 5 days or 7 days, and that the cells can be in culture for weeks (see Examples 2-7). Regarding claims 12 and 30-31, Hartwell teaches the method and system is useful with chronic lymphocytic leukemia (CLL) cells that comprise both B cells and T cells (see paragraphs 169-172).
Hartwell does not teach that the teach that the bone marrow stromal cells are in the presence of IL-15 and CpG. Hartwell does not exemplify using the screening system with CLL cells that comprise both B cells and T cells.
Regarding claims 12-14, Purroy teaches for co-culture of primary CLL cells with BMSCs, expression of CD40 ligand and CpG ODN in the BMSC provides a physiologic and immunophenotypic characteristic environment for proliferating CLL cells that similar to what is found in vivo, which allows for an easily reproducible system for the ex vivo testing of new drugs specifically targeting this clinically relevant compartment of CLL cells (see abstract and page 7633).
Regarding claims 12-14, Slinger teaches that proliferation of CLL cells can be enhanced by both CD40 ligand or 15 ng/ml IL-15, both of which are present in the CLL microenvironment, and that both work in tandem with CpG (see page 2601, 2602 col. 2 and Figure 2). Regarding claims 12-14, Slinger teaches the amount of exogenous CpG that is useful to add to cell culture is 1.5 μg/ml, and the amount of exogenous IL-15 that is useful to add to cell culture is 15 ng/ml (see page 2602)
It would have been obvious to combine Hartwell with Purroy and Slinger to include of exogenous IL-15 and CpG with Hartwell’s BMSCs in Hartwell’s screening method with CLL cells. A person of ordinary skill in the art would have had a reasonable expectation of success in including exogenous IL-15 and CpG with Hartwell’s BMSCs in Hartwell’s screening method with CLL cells because Purroy teaches CD40 ligand and CpG ODN in BMCS specifically supports CLL cells, while Slinger teaches proliferation of CLL cells can be enhanced by both CD40 ligand or exogenous IL-15, both of which are present in the CLL microenvironment, and that both work in tandem with CpG, and that cells can also be treated with exogenous CpG. The skilled artisan would have been motivated to include exogenous IL-15 and CpG with Hartwell’s BMSCs in Hartwell’s because Purroy teaches CD40 ligand and CpG ODN in BMSCs provide an environment for proliferating CLL cells that similar to what is found in vivo, and Purroy teaches that providing primary CLL cells with a similar to what is found in vivo allows for an easily reproducible system for the ex vivo testing of new drugs specifically targeting this clinically relevant compartment of CLL cells, while Slinger teaches proliferation of CLL cells can be enhanced by both CD40 ligand or exogenous IL-15, both of which are present in the CLL microenvironment, and that both work in tandem with CpG which can also be exogenously added to culture systems, and therefore it is obvious to use either CD40 ligand or exogeneous IL-15 with exogeneous CpG treatment. Furthermore, the Slinger reference establishes that they are functional equivalents, and therefore they are obvious to substitute.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Response to Arguments
Applicant's arguments filed 6/18/2025 have been fully considered, but they are not persuasive.
Applicant alleges hindsight reasoning alleging that none of the cited references contemplate or suggest any specific combinations of growth factors with specific co-culture cell types to be clinically relevant on drug selection for the CLL or lymphoma patients. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, as stated above, the primary reference Hartwell specifically teaches that their leukemia/BMSC co-culture assay method allows for the selection of clinically relevant on drug for the treatment of leukemia patients in a clinic, that it is useful to include various factors and cytokines with the cultured cells, and that the type of leukemia may be chronic lymphocytic leukemia (CLL). Therefore, each of these features which applicant alleges are based on hindsight reasoning are specifically contemplated by the primary reference, and therefore this argument is not persuasive.
Applicant highlights that many growth factors were known in the art to make CLL cells survive and proliferate ex vivo and at least 9 have been reported in the literature, including the two (CpG, IL15) used in the claimed invention. Applicant then alleges that based on the number of possible combinations of these 9 factors that are known in the art to be useful, there would not be a reasonable expectation of success in selecting only the two claimed known growth factors (CpG, IL15). Similarly, applicant alleges that there are 3 other cell types besides BMSCs that are known to be useful, which further increases the number of possible useful combinations. To support this position, Applicant points to the attached Declaration by Wang, an inventor on the instant application, wherein inventor Wang provides their opinion that it would not be obvious to select the specific combination of the factors CpG & IL15 with BMSCs for culture. As an initial matter, it is noted that no other growth factors are excluded from the claimed method, and therefore the claimed method is broad to include any combination of known growth factors, as long as said combination includes at a minimum CpG and IL15. It is also noted that even applicant acknowledges that the use of both CpG and the use of IL15 for supporting survival and proliferation ex vivo is known in the prior art, and that it is known that BMSCs are useful in co-culture with CLL cells. Just because there are other known useful growth factors and cell types, does not make it unobvious to use any of these known growth factors or cell types. Importantly, the rejection above does provide both teaching and motivation to specifically include both CpG and IL15, and to specifically use them with BMSCs. Specifically, as stated above, Purroy teaches CD40 ligand and CpG ODN in BMCS specifically supports CLL cells, while Slinger teaches proliferation of CLL cells can be enhanced by both CD40 ligand or exogenous IL-15, both of which are present in the CLL microenvironment, and that both work in tandem with CpG, which can also be added exogenously. The skilled artisan would have been motivated to include exogenous IL-15 and CpG with Hartwell’s BMSCs in Hartwell’s because Purroy teaches CD40 ligand and CpG ODN in BMSCs provide an environment for proliferating CLL cells that similar to what is found in vivo, and Purroy teaches that providing primary CLL cells with a similar to what is found in vivo allows for an easily reproducible system for the ex vivo testing of new drugs specifically targeting this clinically relevant compartment of CLL cells, while Slinger teaches proliferation of CLL cells can be enhanced by both CD40 ligand or exogenous IL-15, both of which are present in the CLL microenvironment, and that both work in tandem with CpG which can also be exogenously added to culture systems, and therefore it is obvious to use either CD40 ligand or exogeneous IL-15 with exogeneous CpG treatment. Furthermore, the Slinger reference establishes that they are functional equivalents, and therefore they are obvious to substitute.
Applicant alleges surprisingly found that only with the combination of BMSC + CpG + IL15, did the ex vivo drug response match well with clinical response of patients to the same drug, citing to Fig.2A-2F and Fig.3A-3D of the instant specification. Applicant also alleges that the cited references show assays for cell proliferation or other properties at the cellular level and fail to show that any results could be expected to translate to clinical use. However, Fig.2A-2F and Fig.3A-3D are limited to comparing one therapeutic agent, ibrutinib (Irb), to a DMSO control in identical BMSC + CpG + IL15 co-culture systems. In other words, these figures do not show any difference between the combination of BMSC + CpG + IL15 and any other co-culture system combination as no other combinations are shown. Furthermore, while applicant alleges that the cited references show assays for cell proliferation or other properties at the cellular level and fail to show that any results could be expected to translate to clinical use, it is noted that all of applicant’s data is also at the cellular level, using in vitro culture systems. Therefore, just as the cited references, all of applicant’s data is using in vitro cell culture systems. Importantly, the claimed method is also limited to a vitro cell culture system. Even so, as stated above, the primary reference Hartwell specifically teaches that this co-culture assay method allows for the selection of clinically relevant on drug for the treatment of leukemia patients in a clinic. For any of these reasons, this argument is unpersuasive.
Conclusion
No claims are free of the art. No claims are allowed.
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 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.
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/S.A.M/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653