27 and 28DETAILED 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 .
Receipt is acknowledged of Applicant’s Amendments and Arguments filed on 11/19/2025.
Claim 14 has been amended.
Claim 26 has been cancelled. Claims 1-13 have been withdrawn from consideration. Accordingly, claims 14, 19-22, 27 and 28 are pending and presented for examination.
Any previous rejections and/or objections not reiterated herein have been withdrawn in view of arguments filed on 11/19/2025. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
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.
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.
Claim(s) 14, 19-22, 27 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Sussanne Danhauser-Riedl et al. (Investigational New Drugs, 11, 187-195, 1993) in view of George et al. (US 8,007,805), Stefania Uccini et al. (Am J Pathology, 150(3), 929-938, 1997), Vera (US 6,409,990), and David R vera et al. (Nuclear Medicine and Biology, 32, 6876-693, 2005).
Danhauser-Riedl discloses a preclinical data suggest that dextran-conjugated doxorubicin (AD-70) has antitumor effects in a variety of tumors. The drug was administered as single dose i.v. every 21-28 days (abstract). Preclinical screening of the 188 dextran/doxorubicin conjugate AD-70 yielded notable antitumor activity. Growth inhibition was observed in various tumor models including Lewis lung, Meth A sarcoma and Walker carcinosarcoma 256 and in mouse leukemia models (L1210, P388), treatment with AD-70 resulted in an increase of life span. Various schedules have been used for administration of AD-70 in preclinical studies (page 188). The structure of AD-70 is shown in Fig. 1.
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Danhauser-Riedl discloses that no objective tumor responses were noted. One patient with malignant fibrous histiocytoma received three courses of AD-70 (12.5 mg/m 2 DOXeq) and showed stable disease for 4 months (page 193). There is evidence that most of the AD-70 conjugate is incorporated into tumor tissue and discloses that the observed cumulation of AD-70 in the tumor tissue might be also due to the natural characteristics of tumors, allowing macromolecules to be taken up more easily. These characteristics and the lower toxicity of AD-70 in animal studies compared with
doxorubicin alone, encouraged the study of this drug in a phase I clinical trial. Additional disclosure includes that coupling of doxorubicin to dextran via a Schiff's base promises to increase selectivity of drug delivery to tumor cells in animal models.
Danhauser-Riedl fails disclose treating sarcoma cancer and a carrier molecule comprising at least one receptor conjugated to dextran via leash in the composition.
George discloses compositions and methods for eliciting immune responses against foreign antigens that are otherwise recognized by the host as "self" antigens, thus breaking host tolerance to those antigens. Antigen presenting cells take up, process, and present the chimeric antigen, eliciting both a humoral and cellular immune response against the desired antigen (abstract). George also discloses that antigen presentation can also be affected via mannose receptors, in place of, or in addition to, utilizing the Fc receptor on antigen presenting cells. The macrophage mannose receptor (MMR), also known as CD206, is expressed on antigen presenting cells such as dendritic cells (DC). This molecule is a member of the C-type lectin family of endocytic receptors. Mannosylated antigens can be bound and internalized by CD206. In general, exogenous antigen is thought to be processed and presented primarily through the MHC class II pathway. However, in the case of targeting through CD206, there is evidence that both the MHC class I and class II pathways are involved (Col. 2 line 50+).Additional disclosure includes methods of treating an immune-treatable condition comprising administering, to a subject in need thereof, a therapeutically effective amount of a chimeric antigen of immune response domain and a target binding domain. In a preferred embodiment, the immune-treatable condition is an infection, especially a chronic infection, or a cancer.
Uccini discloses a study showing the Kaposi’s sarcoma cells express the macrophage-associated antigen mannose receptor and develop in peripheral blood cultures of kaposi’s sarcoma patients (Title). The mannose receptor (MR) is a surface 175-kd C-type lectin containing eight carbohydrate recognition domains with broad specificity for sugars and a fibronectin type 11-like domain. In the study Uccini provide evidence that KS cells express the MR. Moreover, because of the possible relation of KS cells with the macrophage lineage, and findings indicate that peripheral blood of KS patients contain macrophage-related cells that can differentiate in culture into adherent spindle cells the antigenic profile of which is highly reminiscent of that of lesional KS spindle cells (page 930). Expression of MR was investigated in 17 biopsies of KS. Immunostaining for MR was detected in 94 + 7% KS cells with spindle morphology in all of the investigated cases (Figure 2a). MR was detected in more than 95% of KS cells in all of the major clinical forms of the disease using three distinct anti-MR MAbs the specificities of which were proven by their ability to precipitate a 180-kd protein from surface biotinylated dendritic cells, to block uptake of FITC-dextran, and to react in an enzyme linked immunosorbent assay with a soluble form of MR. Intense and diffuse expression of MR in KS spindle cells is an antigenic trait that relates them to macrophages/dendritic cells, as so far the molecule has not been detected in other cell types. The histology of KS lesions is characterized by nodular proliferations of KS spindle cells and by slit-like and vascular spaces lined by endothelial-like cells (page 935).
Vera discloses macromolecular carriers for delivery of drugs and diagnostic agents. The carrier molecule comprises a backbone derived from polysaccharide, preferably dextran with at least one chemical group conjugated to the backbone and the backbone having affixed thereto a plurality of leash groups having structure -O(CH₂)₃-S(CH₂)₂-NH₂. The chemical group is selected from a variety of compound having useful therapeutic or diagnostic uses, including chelators, receptor ligands, lectins, monosaccharides, radiosensitizer (abstract and Col. 2 lines 30-55). In preferred embodiments, the backbone carries both a ligand having a specific affinity for a given tissue or cell type, and a chelator molecule. The chelator for use includes DOTA, MAG3 (for complexation with the radioelement Technetium-99m, and DTPA. DOTA is preferred because its geometry conveniently and tightly accommodates the gadolinium atom, which can be used for both Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) (Col. 3 line 12-22). The carrier molecule includes the following compounds: (Figure 6 and 7).
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The conjugates of dextran to mannose or galactose and to different radiolabeled chelates for imaging liver tumors. The conjugation of therapeutic agents to dextran allows therapy of disorders such as cancer or hepatitis (figures 2, 6-9, 13), attachment of receptors substrates or ligands for tissue specific immunotherapy and attachment of peptides and mono- or polysaccharides for targeting to specific receptors, examples 3-6, column 7, line 5-30). Mannose and galactose are capable of specifically binding to CD206 and cancer and hepatitis can be considered as CD206 expressing cell-related disorders. Additional disclosure includes that useful feature in which the backbone of the macromolecule is dextran and dextran has an excellent safety record, extensive human-use of dextran increases the probability that the delivered drug or diagnostic agent will also be nontoxic and the chemical groups may be directly or indirectly useful by permitting targeting to a given cell or tissue type such that another functional moiety attached to the backbone may perform the affirmative or negative function desired.
Vera discloses optically labeled receptor-binding probe consisting of a dextran backbone to which are attached multiple units of the chelator DTPA and multiple units of a fluorescent reporter based on the indocyanine fluorophore. The DTPA is labeled with 99mTc for nuclear imaging (page 688 and Fig. 1). The optical imaging was performed after intramuscular injection of Cy5.5-DTPA-dextran or Cy5.8-DTPA- galactosyl-dextran via a tall vein. Heart and liver ROI intensities for each image were used to generate two time-intensity curves, wherein heart curve displays rapid clearance, and liver curves exhibited a rapid uptake phase and targeted agent also accumulated in the urinary bladder (page 689-699 and Fig 4).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to choose compositions and methods for eliciting immune responses against foreign antigens as taught by George for treating an immune-treatable condition to be incorporated into the dextran-conjugated doxorubicin (AD-70) composition of Danhauser-Riedl. A person of ordinary skill in the art would have been motivated to do so because George teaches that the macrophage mannose receptor (MMR), also known as CD206, is expressed on antigen presenting cells such as dendritic cells (DC) and Mannosylated antigens can be bound and internalized by CD206. In general, exogenous antigen is thought to be processed and presented primarily through the MHC class II pathway. However, in the case of targeting through CD206, there is evidence that both the MHC class I and class II pathways are involved (Col. 2 line 50+). Further Uccini teaches that Kaposi’s sarcoma cells express the macrophage-associated antigen mannose receptor and develop in peripheral blood cultures of kaposi’s sarcoma patients (Title). In the study Uccini provide evidence that KS cells express the MR. Moreover, because of the possible relation of KS cells with the macrophage lineage, and findings indicate that peripheral blood of KS patients contain macrophage-related cells that can differentiate in culture into adherent spindle cells the antigenic profile of which is highly reminiscent of that of lesional KS spindle cells (page 930). Thus, in view of the teachings of Danhauser-Riedl, George and Uccini, there would have been a reasonable expectation that composition comprising dextran-conjugated doxorubicin (AD-70) and the macrophage mannose receptor (MMR), also known as CD206, would be used in a method for treating an immune-treatable condition, the immune-treatable condition is an infection, especially a chronic infection, a cancer or Kaposi’s sarcoma.
It would have been obvious to one of ordinary Skill in the art at the time the invention was made to incorporate dextran backbone having leash and detectable moiety (Cy-3) into Danhauser-Riedl's composition. The person of ordinary skill in the art would have been motivated to make those modifications because Vera teaches a compositions and methods pertaining io the targeting of drugs and diagnostic agents to specific tissues using a macromolecular delivery vehicle and when combined or conjugated with therapeutic agents, is especially useful for cardiovascular and/or tumor imaging (Col. 6 line 50+) and reasonably would have expected success because both cited reference discloses compositions that can be used in the same field of endeavor such as macrophage mannose receptor (MMR) is composed of 4 single subunit with N and O linked glycosylations for detecting, identifying, diagnosing, and treating cancer.
Conclusion
No claims are allowed at this time.
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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/J.R.S/Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618