DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s response and amendments received July 14, 2025 are acknowledged.
Claims 3, 5, and 12-18 have been canceled.
Claims 1, 6, 7, 8, and 11 have been amended.
Claim 19 has been added.
Claims 1, 2, 4, 6-11, and 19 are pending in the instant application.
Claims 1, 2, 4, 6-11, and 19 are under examination in this office action.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
The rejection of claims 1, 2, 4, 6, 7, 11, 12, and 14 under 35 U.S.C. 102(a)(1) as being anticipated by Mao has been withdrawn in view of applicant’s claim amendment received July 14, 2025 which require targeting the immunoliposome to antigenic targets not disclosed by the cited art.
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.
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, 4, 6-11, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Mao (of record) in view of CN 116118 (of record) and in view of Topp et al. (of record).
Mao discloses dual ligand immunoliposomes (immunoliposomes which display two antibodies on their surface) wherein the pairs of antibodies on such constructs include anti-CD37 in combination with either anti-CD19 or anti-CD20 (see entire document, particularly Chapter 2). Notably, such constructs are disclosed as being useful for treating leukemia and killing cells via antibody crosslinking alone as no anti-cancer payloads were delivered (i.e. a “blank” liposome, see for example section 2.3.7, Figure 2.8, and page 65). Note that ratios of the two antibodies different from 1:1 were made and tested (see in particular section 2.3.4 and Figure 2.5). Such immunoliposomes contain phosphatidylcholine and cholesterol, and were made by conjugation of the antibodies to maleimide groups in the lipids (see particularly sections 2.2.1 and 2.2.7 as well as Chapter 1 and Figure 1.5). Antibodies used in targeting immunoliposomes are disclosed as being full length antibodies as well as antigen binding fragments thereof including Fab’ and scFv (see for example pages 13 and 18-21). Indeed, Mao explicitly teaches on page 21 that “To overcome immunogenicity and also to maximize the binding efficiency, F(ab’)2, Fab’, and scFv fragments lacking the Fc domain but with complementary activating regions are useful or ILP immobilization” (note that “ILP” stands for immunoliposome, see for example page 18 pf Mao et al). Various liposome formulation components, including egg phosphatidylcholine, are disclosed (see for example section 1.2.1.1 as well as Figure 1.2 and Table 1.1). Such inventions differ from that which is presently claimed in that the “auxiliary” antibodies binding lymphocytes in the compositions of Mao bind to B cells rather than to T cells expressing CD3 as is presently claimed.
The ‘118 document discloses making and using bispecific liposomes that surface express an anti-tumor antibody and an anti-T cell antibody to treat cancer (see entire translation, particularly page 3, the sentence spanning pages 3 and 4, and the paragraph immediately preceding the Example on page 5). Notably the anti-T cell antibody is disclosed as being the well-known anti-CD3 antibody named OKT3 (see the top of page 6). The ratio between the two antibodies can vary, with the working example disclosing a 5:1 ratio between the anti-tumor antibody and the anti-CD3 antibody (see particularly the working example).
Topp et al. disclose that the bispecific T cell engager blinatumomab which binds CD3 and CD19 and brings CD3 expressing T cells into contact with CD19 expressing tumor cells is effective in treating acute lymphoblastic leukemia (ALL) in human patients (see entire document, particularly the abstract).
Therefore, it would have been obvious to a person of ordinary skill to modify the antibody targeted liposomes of Mao to target other antigen specificities such as CD3 in order to redirect killing to tumor types distinct from those taught by Mao. Artisans would have been motivated to do so since immunoliposomes targeting CD3 and tumor antigens were known for treating leukemia in the art as evidenced by the ‘118 document, with the combination of anti-CD3 and anti-CD19 being highly desirable in treating leukemia as taught by Topp et al. In particular, artisans would know that targeting CD19 and CD3 in the same compound successfully targets CD3 expressing T cells to CD19 expressing B cell tumors in human leukemia as taught by Topp et al. and that such killing activity occurs in the absence of additional drugs being conjugated to the bispecific T cel engager. Given that dual ligand immunoliposomes not loaded with chemotherapeutics can be successfully used to treat cancers including leukemia as taught by Mao, it would be obvious that other antibody pairs known to treat cancers including leukemia could be combined in immunoliposomes and used for the same purpose, with the advantage of dual ligand immunoliposomes over traditional bispecific reagents being that the ratio between the two antibodies can readily varied and optimized in an immunoliposome as readily demonstrated by Mao and the ‘118 document whereas the bispecific T cell engagers of Topp et al. are fixed at a 1 to 1 ratio which cannot be optimized for therapeutic purposes. Given the use of liposomes comprising two antibodies to different antigens as shown by both Mao and the ‘118 document, and the ability of dual specificity regents to kill targets in the absence of additional chemotherapeutic agents as shown by Mao and Topp et al., artisans would have a reasonable expectation of success when making blank liposomes that display two different antibodies on their surface at ratios greater than 1 to 1. Note further that artisans would also be motivated to use antigen binding fragments of antibodies, such as scFv, rather than whole antibody in order to gain the advantage of reduced immunogenicity as taught by Mao.
Applicant's arguments filed July 14, 2025 have been fully considered but they are not persuasive. Applicant argues on multiple grounds. Applicant argues that the independent claim has been amended to recite that the auxiliary antibody binds CD3 while the predominant antibody binds either CD19 or LGR5, that both the predominant and auxiliary antibodies are present in the form of an antigen binding fragment chosen from the group consisting of Fab’, F(ab’)2, Fab, and scFv, and argues that the cited art fails to teach antigen binding fragments of antibodies conjugated to liposomes to make immunoliposomes. Applicant also asserts that the compositions of the independent claim are unexpectedly stable, points to Table 1 of the instant specification to support such an assertion, and argues that working examples 2-5 demonstrate that the claimed invention works in killing cancer target cells. Based on all of this, applicant believes the rejection should be withdrawn.
These arguments are not persuasive. As set forth in the rejection, contrary to applicant’s assertions Mao does teach the use of antigen binding fragments of antibodies conjugated to liposomes as well as their advantageous property of being less immunogenic as compared to similar compositions which additionally comprise the Fc domain of an antibody. With regard to applicant’s assertions of unexpected results, applicant is reminded that the instant claimed invention is quite broad in that any antibodies specific for the desired targets are encompassed as are a wide variety of possible compositions for the lipids in the liposome whereas the working examples used exact sequenced antibodies in exact ratios in liposomes of exact composition. Thus the data of the working examples does not reasonably seem to be extrapolatable to all of the conditions encompassed by the claimed invention. Further, applicant has argued that immunoliposomes made from antigen binding fragments are unexpectedly more stable than those made from whole antibody yet data comparing immunoliposomes made from whole antibody as compared to scFv does not appear to be disclosed. Further, it is well known in the art that the stability of scFv is strongly dependent upon the structure of the VH and VL of the antibody made into a scFv with some constructs showing instability wile others are perfectly fine when conjugated to liposomes (see for example the entirety of Chen et al., particularly section 4 “Stability of ScFv constructs”). Thus applicant’s alleged unexpected results would not reasonably be expected by artisans to extend to antibody constructs outside those of the working examples and even regarding the working examples the “unexpected stability” cannot reasonably be ascertained as data comparing scFv to whole antibody or other antibody antigen binding fragments like Fab’ are not disclosed in the specification. As such applicant’s arguments cannot reasonably be found to be persuasive. .
No claims are allowable.
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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Michael Szperka
Primary Examiner
Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641
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