DETAILED ACTION
Status of the Claims
Claims 1-14 are pending in the instant application and are being examined on the merits in the instant application.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.
Priority
The instant Application is a Divisional application of 15/164,994 and claims benefit to U.S. Provisional Application No. 62/167,563. The U.S. effective filing date has been determined to be 05/26/2016, the filing date of the U.S. Application No. 15/164,994. The examiner finds no support for the patient class of “a subject diagnosed with Alzheimer’s Disease” or “systemically delivering a nanoparticle to the subject via intravenous or intraperitoneal injection” in U.S. Provisional Application No. 62/167,563.
Claim Objections
The specification remains objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: “the nanoparticle including a core that comprises a first (pyridine-2-thiol)-co-poly(ethylene glycol) copolymer that includes a biologically active compound for use in treatment of Alzheimer’s Disease conjugated to the first copolymer via substitution at the pyridine-2-thiol pendant groups of the first copolymer, a second (pyridine-2-thiol)-co-poly(ethylene glycol) copolymer that includes a first blood brain barrier transporter conjugated to the second copolymer via substitution at the pyridine-2-thiol pendant groups of the second copolymer, and a third (pyridine-2-thiol)-co-poly(ethylene glycol) copolymer, the core comprising the first, second and third copolymers crosslinked with one another, the nanoparticle further including a second, different blood brain barrier transporter conjugated to a surface of the nanoparticle via substitution at (pyridine-2-thiol) pendant groups of the third copolymer” (instant claim 1, lines 5-15). The instant Specification does not provide proper antecedent basis for a first copolymer, a second copolymer, and a third copolymer or the structural relationship recited in the claim(s).
Response to Arguments:
Applicant's arguments filed 11/12/2025 have been fully considered but they are not persuasive.
Applicant’s arguments, and amendment to p. 10, paragraph [0037], are acknowledged. However, the does not find any support for the claim term “core” or the structural relationship between the core and the first, second and third copolymers. The examiner finds no support for a first copolymer conjugated to “a biologically active compound” in the core. The examiner finds no support for the second copolymer conjugated to a first blood brain barrier transporter in the core.
Rather the Specification clearly discloses that: “According to one embodiment, disclosed are nanoparticles suitable for delivery of materials across the blood brain barrier. More specifically, the nanoparticles include a biocompatible hydrophilic polymer and two (or more) types of surface ligands that can encourage transport across the blood brain barrier and then be detached from the nanoparticles by acidic pH and/or high redox potential as may be found in the lysosome or following crossing of the blood brain barrier so as to release the payload carried by the nanoparticles. The nanoparticles can also include a biologically active compound such as a drug, e.g., encapsulated in the nanoparticle or attached to the surface of the nanoparticle, for delivery following crossing of the blood brain barrier by the nanoparticles.” ([0004]). And that: “In one particular embodiment, the Dual Targeted and Dual Responsive Nanoparticles (DTDRN) can be functionalized to include scopine in conjunction with glutathione.” ([0026]). And further that: “Through conjugation of both scopine and glutathione to a nanoparticle delivery system as disclosed herein, improved delivery of biologically active compounds across the blood brain barrier can be achieved.” ([0026]). And further that: “For instance, one or both of the functional ligands can be surface conjugated to the nanoparticles following crosslinking and particle formation to form the delivery system that can facilitate nanoparticle penetration through the blood brain barrier.” ([0040]). And further that: “The payload (i.e., the drug compound to be delivered to the brain) can be encapsulated into the nanoparticle by hydrophobic interaction or chemically conjugated to the surface through, e.g., -S-S-, -CONH-, or -COO- bonds.” ([0042]). That is the Specification discloses the two blood brain barrier ligands conjugated to the surface to facilitate nanoparticle penetration through the blood brain barrier. And further discloses the “biologically active agent” is either encapsulated or conjugated to the surface.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 3-7, 11 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over XU (US 2014/0011760; published January, 2014) in view of Ying et al. ("Dual-targeting liposomes improves the therapeutic efficacy of bran glioma in animals," 2010; ELSEVIER, Journal of Controlled Release, Vol.141, pp. 183-192); Riganti et al. (“Nanoparticle- and Liposome-carried Drugs: New Strategies for Active Targeting and Drug Delivery Across Blood-brain Barrier,” 2013, Current Drug Metabolism, Vol. 14, pp. 625-640); Salem et al. (“Targeting brain cells with glutathione-modulated nanoliposomes: in vitro and in vivo study, 2015, Dovepress; Drug Design, Development and Therapy, Vol. 9, pp. 3705-3727); Wang et al. ("Scopine as a Novel Brain-Targeting Moiety Enhances the Brain uptake of Chlorambucil," 2014, ACS; Bioconjugate Chemistry, Vol 25, pp. 2046-2054) and Bernardi et al. (“Indomethacin-loaded lipid-core nanocapsules reduce the damage triggered by Aβ1-42 in Alzheimer’s disease models,” 2012; Dove Medical Press; International Journal of Medicine, Vol. 7, pp. 4927-4942).
Applicants Claims
Applicant claims a method for delivering a biologically active agent across the blood brain barrier of a subject diagnosed with Alzheimer’s Disease, the method comprising: systemically delivering a nanoparticle to the subject via intravenous or intraperitoneal injection, the nanoparticle including a core that comprises a first (pyridine-2-thiol)-co-poly(ethylene glycol) copolymer that includes a biologically active compound for use in treatment of Alzheimer’s Disease conjugated to the first
(pyridine-2-thiol)-co-poly(ethylene glycol) copolymer via substitution at the pyridine-2-thiol pendant groups of the first (pyridine-2-thiol)-co-poly(ethylene glycol) copolymer, a second (pyridine-2-thiol)-co-poly(ethylene glycol) copolymer that includes a first blood brain barrier transporter conjugated to the second (pyridine-2-thiol)-co-poly(ethylene glycol) copolymer via substitution at the pyridine-2-thiol pendant groups of the second (pyridine-2-thiol)-co-poly(ethylene glycol) copolymer, and a third (pyridine-2-thiol)-co-poly(ethylene glycol) copolymer, the core comprising the first (pyridine-2-thiol)-co-poly(ethylene glycol) copolymer, the second (pyridine-2-thiol)-co-poly(ethylene glycol) copolymer and the third (pyridine-2-thiol)-co-poly(ethylene glycol) copolymer crosslinked with one another, the nanoparticle further including a second, different blood brain barrier transporter conjugated to a surface of the nanoparticle via substitution at (pyridine-2-thiol) pendant groups of the third (pyridine-2-thiol)-co-poly(ethylene glycol) copolymer; wherein following the systemic delivery of the nanoparticle, the nanoparticle crosses the blood brain barrier; and wherein following the crossing of the blood brain barrier, disulfide bonds of the first (pyridine-2-thiol)-co-poly(ethylene glycol) copolymer, the second (pyridine-2-thiol)-co-poly(ethylene glycol) copolymer and the third (pyridine-2-thiol)-co-poly(ethylene glycol) copolymer are degraded, thereby releasing the biologically active compound and detaching the first and second blood brain barrier transporters from the nanoparticle in the brain of the subject, and wherein the biologically active compound comprises one or more of n-acetyl cysteine, pyrrolidine dithiocarbamate, diethyldithiocarbamate, resveratrol, indomethacin, curcumin, and sulindac (instant claim 1). And wherein the first blood brain barrier transporter is scopine and the second blood brain barrier transporter is glutathione (claim 4). And wherein one or more of the first, second, and third copolymers comprise (pyridine-2-thiol) ethyl acrylate-co-poly(ethylene glycol) (PDA-PEG) (claim 5). And wherein one or more of the first, second, and third copolymers comprise (pyridine-2-thiol) ethyl methacrylate-co-poly(ethylene glycol), N-(2-(pyridin-2-yldisulfanyl)ethyl) acrylamide-co-poly(ethylene glycol), N-(2-(pyridin-2-yldisulfanyl)ethyl)methacrylamide-co-poly(ethylene glycol), or ethyl (2-(pyridin-2-yldisulfanyl)ethyl) carbonate-co-poly(ethylene glycol) (claim 7).
Determination of the scope
and content of the prior art (MPEP 2141.01)
XU teaches novel polymers and the preparation of nanogel drug cocktails (see whole document), and particularly teaches the methods include polymerizing 2-(pyridin-2-yldisulfanyl)ethyl acrylate (PDSA), a (pyridine-2-thiol) ethyl acrylate monomer, with poly(ethylene glycol)methacrylate (PEGMA) via free radical polymerization to form the copolymer (abstract) (instant claim 1, lines 1-3). XU teaches the copolymer species including:
PNG
media_image1.png
547
392
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Greyscale
(Figure 6B), wherein “a ratio of x to y that is about 100:1 to about 1:100 (i.e., the molar ratio of the PDSA monomer to the PEG MA monomer is about 100: 1 to about 1: 100).” ([0036])(instant claim 1, a first/second/third (pyridine-2-thiol)-co-poly(ethylene glycol) copolymer; instant claims 5-7). The examiner notes that the PDSA monomer includes a disulfide (-S-S-) bond which labile to redox potential ([0053]) which can be used for drug release ([0063]-[0066]). And further that “After polymerizing, the copolymer can be reacted with a thiol monomer that contains a carbon-bonded sulfhydryl to modify end groups on a first portion of the 2-(pyridin-2-yldisulfanyl) ethyl acrylate repeating units. Thereafter, the copolymer can be crosslinked, and a drug can then be loaded into the crosslinked copolymer.” (abstract), and further that “in particular embodiments, the method can further include crosslinking the copolymer via a thiol-disulfide exchange reaction to form a crosslinked copolymer. A drug (or a combination of drugs) can then be loaded into the crosslinked copolymer.’ ([0006])(instant claim 1, "first, second and third copolymers crosslinked with one another").
XU teaches crosslinking to form nanogels "Through this crosslinking reaction, a nano gel polymeric material is formed with intramolecular disulfide bonds resulting in the assembly of subcompartments while intermolecular disulfide bonds stabilize the multicompartment nanogel structure through disulfide bonds between subcompartments." ([0048]). More specifically, XU teaches "Crosslinking of RPDSEG" ([0044]) in which "The RPDSEG polymer can then be crosslinked via a second thiol-disulfide exchange reaction that bonds a portion of the remaining (i.e., unsubstituted) end groups of the PDSA monomer in the PDSEG polymer with each other. For example, the crosslinking reaction can occur via disulfide bonds cleavage followed by aerial oxidation." ([0045]). And that "A new type of polymer, poly[(2- (pyridin-2-yldisulfanyl)-co-[poly(ethylene glycol)]] (PDSEG), was developed that containing both ester and disulfide bonds, which are labile to acidic pH and redox potential, respectively. On this basis, a pH and redox dual responsive nanoparticle was fabricated and aimed to fully take advantage of its use in a drug cocktail while eliminating the toxic side effects associated with the drug combination." [ emphasis added] ([0053]).
XU further teaches that the PDSA-mPEG copolymer (PDSEG) was then modified with a aVβ3 integrin targeting moiety, cyclo(Arg-Gly-Asp-D-Phe-Cys) (cRGD) peptide, by thiol-disulfide exchange reaction (Figure 6A-6C, [0065], also see [0072]). And further that "To enhance the nanogel targeting to cancer cells, cRGD peptides were conjugated with the PDSEG polymer by thiol-disulfide exchange reaction." ([0067]) ( instant claim 1, "the first pendant groups comprising a first blood brain barrier transporter conjugated to the backbone via a first pyridine-2-thiol group").
XU further teaches that: “For example, drug loaded nano gels can be suspended in saline and administered to a cancer patient through intravenous infusion or intravenous bolus injection.” ([0052]). While XU does not expressly disclose “systemically delivering” (claim 1, line 3), this is clearly implied by “intravenous infusion or intravenous bolus injection” (MPEP §2144.01).
XU teaches that: “Drug loaded nanogels, ND (nano doxorubicin (DOX)) and NCPD (nano-cocktail of paclitaxel (PTX) and DOX), were fabricated by dialysis after the crosslinking reaction initiated by the addition of predetermined amount of tris(2-carboxyethyl)phosphine (TCEP). The formed intramolecular disulfide bonds triggered the assembly of the subcompartment of the nanogel while the disulfide bonds between subcompartments, mainly due to intermolecular disulfide bonds, stabilized the multicompartment nanogel structure.” ([0065]).
XU further teaches that: “Since both ND and NCPD were made of the same polymer and fabricated from the same assembly method (except the loaded drugs), for simplification we used ND nano gel as a model to investigate the NCPD nanogel response to the stimuli of both pH and redox potential and its cellular uptake and intracellular trafficking. To validate the pH responsive property of the nanogel, we carried out the drug release kinetic measurement at both pH 7.4 and 5.5 to mimic the physiological and lysosomal pH. […] However, there was no significant increase of drug released in the acetic buffer containing 10 mM DTT, which we think is due to both acidic pH and redox potential resulted in same side chain cleavage regardless the breaking points. To further investigate the intracellular behavior of the redox sensitive nanogel, we added TCEP to simulate the intracellular elevated glutathione condition. FIG. 28 showed that ND nanogel quickly increased its size from 113 nm to 262 nm after 5 hr incubation in PBS (pH 7.4 containing 1 mM of TCEP). Transmission electron microscopy also proved the enlargement of the nanogel (FIG. 2C). Since the ND nanoparticle is negatively charged, the cleavage of disulfide bonds will result in the swelling of the nanogel due to the repulsion force between charged polymer blocks. We expect the redox responsive swelling of the nano gel will break up the lysosome membrane and facilitate its trafficking to nuclei.” [emphasis added]([0066])(instant claim 14).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of XU is that XU does not expressly teach targeting the blood brain barrier (BBB) with dual targeting moieties including scopine and glutathione (claims 3-4) or the inclusion of an active for treating Alzheimer’s Disease (patient class & drug, claims 1-2).
Ying et al. teaches liposomes with the targeting agent p-aminophenyl-α-D-mannopyroside (MAN) and transferrin (TF), and particularly that "Chemotherapy for brain glioma has been of limited value due to the inability of transport of drug across the blood-brain barrier (BBB) and poor penetration of drug into the tumor. For overcoming these hurdles, the dual-targeting daunorubicin liposomes were developed by conjugating with p-aminophenyl-α-D-mannopyranoside (MAN) and transferrin (TF) for transporting drug across the BBB and then targeting brain glioma. The dual-targeting effects were evaluated on the BBB model in vitro, C6 glioma cells in vitro, avascular C6 glioma tumor spheroids in vitro, and C6 glioma bearing rats in vivo, respectively. After applying dual targeting daunorubicin liposomes, the transport ratio across the BBB model was significantly increased up to 24.9%. [ ... ] The median survival time of tumor bearing rats after administering dual-targeting daunorubicin liposomes (22 days) was significantly longer than that after giving free daunorubicin (17 days, P=0.001) or other controls. In conclusion, the dual targeting daunorubicin liposomes are able to improve the therapeutic efficacy of brain glioma in vitro and in animals." [emphasis added](abstract).
Ying et al. teaches "Considering the specific affinity to the GLUTl, p-aminophenyl-α-D-manno-pyranoside (MAN) which is a kind of mannose analog was incorporated onto the surface of liposomes in the present study." (p. 184, col 1, lines 3-6). And that "TF can be transported into the cells by binding with transferrin receptor (TfR), which acts as a carrier for TF in maintaining iron homeostasis in the cells. [ ... ] Accordingly, the above aspects would be beneficial for brain tumor targeting as the drug-loaded liposomes modified with TF may contribute to enhance both the transport of drug across the BBB and endocytosis of drug by brain tumor cells." (p. 184, col. 1, 2nd paragraph). Ying et al. further describes the liposome nanoparticle including MAN and TF (Figure 1).
Riganti et al. teaches that: “The blood-brain barrier (BBB), the unusual microvascular endothelial interface between the central nervous system (CNS) and the circulatory system, is a major hindrance to drug delivery in the brain parenchyma. Besides the absence of fenestrations and the abundance of tight junctions, ATP-binding cassette (ABC) transporters critically reduce drug entry within the CNS, as they carry many drugs back into the bloodstream. Nanoparticle- and liposome-carried drugs, because of their increased cellular uptake and reduced efflux through ABC transporters, have been developed in recent times to circumvent the low drug permeability of the BBB.
This review discusses the role of ABC transporters in controlling drug penetration into the brain parenchyma, the rationale for using nanoparticle- and liposome-based strategies to increase drug delivery across the BBB and new therapeutic strategies for using nanoparticle- and liposome-carried drugs in different conditions, ranging from CNS tumors and neurodegenerative diseases to viral infections and epilepsy.” (see whole document, particularly the abstract).
Riganti et al. teaches that: “Nanotechnologies can further increase the distribution to CNS tumors by designing dual-targeted NPs, i.e. NPs which recognize BBB and CNS tumor cells at the same time. Docetaxel-carrying NPs conjugated with the TGN peptide, selected by phage-display as a molecule targeting the BBB, and with an aptamer targeting the surface of glioma cells, has been recently proven to reach high intratumor concentrations and cytotoxic efficacy.” (paragraph bridging pp. 630-631). And further that: “A similar “dual-targeting” approach – i.e. the dual ability to cross the BBB and target CNS cells – can be also achieved by conjugating liposomes with more than one ligand, i.e. one ligand specific for endothelial cells and the other specific for CNS cells. For instance, PEG-immunoliposomes conjugated with an anti-Tf receptor antibody were further conjugated with an anti-Aβ antibody: these dual-targeting liposomes were well delivered across the BBB and directed to the Aβ peptide in the brain parenchyma [122], thus appearing as potential tools against Alzheimer’s disease (AD). Dual targeting liposomes carrying daunorubicin, conjugated with Tf and p-aminophenyl-alpha-D-manno-pyranoside (which recognize the BBB and glioma surface, respectively), were successfully used in glioma-bearing animals [123]. Dual targeting also increases the uptake of liposomes by BBB cells, because it may overcome the saturation limit observed when endocytosis is single receptor dependent [124].” (p. 632, col. 1, 2nd paragraph). The examiner notes that the reference [123] in Riganti et al. is Ying et al. (relied on herein). Given that both dual-targeting for treating brain cancer (glioma), as suggested by Ying et al., and Alzheimer’s disease, as suggested by Riganti et al. together with brain cancer, it would have been reasonably apparent to one of ordinary skill in the art that targeting brain cancer (XU teaching cancer targeting but not specifically brain cancer), as suggested by Ying et al., and Alzheimer’s would have been obvious as they both involve dual-targeting of the BBB, as clearly suggested by Riganti et al.
Salem et al. teaches Targeting brain cells with glutathione-modulated nanoliposomes (title, see whole document), and particularly teaches that: “Nonetheless, the drug delivery to brain is very challenging. These challenges are classified into chemical and physical barriers. The blood–brain barrier (BBB) is an example of both physical and chemical barriers, where tight junction among endothelial cells of BBB presents physical barrier and also endothelial cells of the BBB produce significant amount of adenosine triphosphate-driven drug efflux transporters, which present chemical barrier. The blood–brain barrier protects the brain by regulating transport in and out of the brain.” (p. 3705, §Introduction, 2nd paragraph). And that: “Recently, many targeting moieties are being used to deliver drug into the brain efficiently. This was recognized with scopine, monoclonal antibody 2C5,15 the OX2616 or R17217 antibodies, glutathione, and anti-transferrin. These moieties were found to enhance the uptake of the pharmaceutical moieties up to 14.25-fold.” (p. 3706, 1st paragraph). And further that: “It has recently been shown that glutathione is coupled with micelles and nanoparticles and showed enormous potential in both targeting and enhancing the drug moieties into brain.” [emphasis added](p. 3706, 2nd paragraph)(instant claims 3-4, glutathione).
Wang et al. teaches scopine as novel brain-targeting moiety (see whole document). Wang et al. teaches that "As expected, the cyclic tertiary amines, especially scopine, were shown to significantly enhance the brain uptake of CHL." [emphasis added]. And "In the cellular uptake study, conjugation of scopine significantly improved the cellular uptake of CHL in both bEnd.3 cells and C6 cells, and the uptake was proven to be energy-dependent, indicating an active mode of transport." (p. 2050, cols. 1-2) (instant claims 2-3, scopine).
Bernardi et al. teaches indomethacin-loaded lipid-core nanocapsules for treatment of Alzheimer’s disease (see whole document). Bernardi et al. teaches that: “Neuroinflammation, characterized by the accumulation of activated microglia and reactive astrocytes, is believed to modulate the development and/or progression of Alzheimer’s disease (AD). Epidemiological studies suggesting that nonsteroidal anti-inflammatory drugs decrease the risk of developing AD have encouraged further studies elucidating the role of inflammation in AD. Nanoparticles have become an important focus of neurotherapeutic research because they are an especially effective form of drug delivery. Here, we investigate the potential protective effect of indomethacin-loaded lipid-core nanocapsules (IndOH-LNCs) against cell damage and neuroinflammation induced by amyloid beta (Aβ)1-42 in AD models. Our results show that IndOH-LNCs attenuated Aβ-induced cell death and were able to block the neuroinflammation triggered by Aβ1-42 in organotypic hippocampal cultures. […] These findings might be explained by the increase of IndOH concentration in brain tissue attained using drug-loaded lipid-core NCs. All these findings support the idea that blockage of neuroinflammation triggered by Aβ is involved in the neuroprotective effects of IndOH-LNCs. These data provide strong evidence that IndOH-LNC treatment may represent a promising approach for treating AD.” (abstract)(instant claim 11).
Regarding the limitation that “detaching the first and second blood brain barrier transporters from the nanoparticle in the brain of the subject” (instant claim 1), it is clear that XU teaches cleavage of the disulfide bonds in “the physiological and lysosomal pH” and under “intracellular elevated glutathione condition”, therefore it would have been prima facie obvious that under those same conditions upon administration the first (Scopine) and second (glutathione) blood brain barrier transporters would have inherently been subjected to cleavage (i.e. detaching the first and second blood brain barrier transporters from the nanoparticle in the brain of the subject)(instant claims 1 and 14).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat Alzheimer’s disease using a dual targeting nanocarrier such as the PDA-SEG taught by XU, because XU teaches treating cancer of which brain cancer is known using dual targeting nanocarriers, as suggested by Ying et al. and Riganti et al., where Riganti et al. clearly suggests the dual brain targeting approach for both brain cancer and Alzheimer’s disease, the targeting species glutathione and scopine both having been known to delivery drugs across the BBB, as suggested by Salem et al. (teaching scopine and glutathione), and Wang et al. (teaching scopine), and further to utilize a known drug for treating Alzheimer’s disease such as indomethacin, as suggested by Bernardi et al. as useful for the same.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because XU teaches nanocarriers for the treatment of cancer (front page, [0009]) for intravenous delivery ([0052]), including methods of making the same, and it would have required no more than an ordinary level of skill in the art to covalently attach (conjugate) glutathione, scopine and an active agent such as indomethacin to the polymers described therein. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. this is pre-AIA
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over XU (US 2014/0011760; published January, 2014) in view of Ying et al.; Riganti et al.; Salem et al.; Wang et al. and Bernardi et al. as applied to claims 1, 3-7, 11 and 14 above, and further in view of Shahripou et al. (“N-acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities,” 2014; Brain and Behavior, Vol. 4, No. 2, pp. 108-122).
Applicants Claims
Applicant claims a method for delivering a biologically active agent across the blood brain barrier of a subject diagnosed with Alzheimer’s Disease, as discussed above. Applicant further claims the biologically active agent comprises n-acetyl cysteine (instant claim 2).
Determination of the scope
and content of the prior art (MPEP 2141.01)
XU teaches novel polymers and the preparation of nanogel drug cocktails, as discussed above and incorporated herein by reference.
Ying et al. teaches liposomes with the targeting agent p-aminophenyl-α-D-mannopyroside (MAN) and transferrin (TF), as discussed above and incorporated herein by reference.
Riganti et al. teaches the role of ABC transporters in controlling drug penetration into the brain parenchyma, the rationale for using nanoparticle- and liposome-based strategies to increase drug delivery across the BBB, as discussed above and incorporated herein by reference.
Salem et al. teaches Targeting brain cells with glutathione-modulated nanoliposomes, as discussed above and incorporated herein by reference.
Wang et al. teaches scopine as novel brain-targeting moiety, as discussed above and incorporated herein by reference.
Bernardi et al. teaches indomethacin-loaded lipid-core nanocapsules for treatment of Alzheimer’s disease, as discussed above in incorporated herein by reference.
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of XU et al. is that XU et al. do not expressly teach the inclusion of an active for treating Alzheimer’s Disease comprising n-acetyl cysteine.
Shahripou et al. teaches N-acetylcystein (NAC) for the treatment of neurological disorders including Alzheimer’s Disease (see whole document, particularly p. 109, Table 1, Alzheimer’s disease).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat Alzheimer’s disease using a dual targeting nanocarrier such as the PDA-SEG taught by XU, because XU teaches treating cancer of which brain cancer is known using dual targeting nanocarriers, as suggested by Ying et al. and Riganti et al., where Riganti et al. clearly suggests the dual brain targeting approach for both brain cancer and Alzheimer’s disease, the targeting species glutathione and scopine both having been known to delivery drugs across the BBB, as suggested by Salem et al. (teaching scopine and glutathione), and Wang et al. (teaching scopine), and further to utilize a known drug for treating Alzheimer’s disease such as indomethacin, as suggested by Bernardi et al. as useful for the same; and further to include n-acetyl cysteine (NAC) as a suitable Alzheimer’s therapeutic agent, as suggested by Shahripou et al.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because XU teaches nanocarriers for the treatment of cancer (front page, [0009]) for intravenous delivery ([0052]), including methods of making the same, and it would have required no more than an ordinary level of skill in the art to covalently attach (conjugate) glutathione, scopine and an active agent such as indomethacin to the polymers described therein. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
Claims 8 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over XU (US 2014/0011760; published January, 2014) in view of Ying et al.; Riganti et al.; Salem et al.; Wang et al. and Bernardi et al. as applied to claims 1, 3-7, 11 and 14 above, and further in view of Zaki et al. (“Pyrrolidine dithiocarbamate protects against scopolamine-induced cognitive impairment in rats,” 2014, ELSEVIER; European Journal of Pharmacology, Vol. 723, pp. 330-338) and Dvorak et al. (“Targeting of Nuclear Factor-kB and Proteasome by Dithiocarbamate Complexes with Metals,” 2007; Current Pharmaceutical Design, Vol. 13, pp. 3155-3167).
Applicants Claims
Applicant claims a method for delivering a biologically active agent across the blood brain barrier of a subject diagnosed with Alzheimer’s Disease, as discussed above. Applicant further claims the biologically active agent comprises pyrrolidine dithiocarbamate or diethyldithiocarbamate (instant claims 8-9, respectively).
Determination of the scope
and content of the prior art (MPEP 2141.01)
XU teaches novel polymers and the preparation of nanogel drug cocktails, as discussed above and incorporated herein by reference.
Ying et al. teaches liposomes with the targeting agent p-aminophenyl-α-D-mannopyroside (MAN) and transferrin (TF), as discussed above and incorporated herein by reference.
Riganti et al. teaches the role of ABC transporters in controlling drug penetration into the brain parenchyma, the rationale for using nanoparticle- and liposome-based strategies to increase drug delivery across the BBB, as discussed above and incorporated herein by reference.
Salem et al. teaches Targeting brain cells with glutathione-modulated nanoliposomes, as discussed above and incorporated herein by reference.
Wang et al. teaches scopine as novel brain-targeting moiety, as discussed above and incorporated herein by reference.
Bernardi et al. teaches indomethacin-loaded lipid-core nanocapsules for treatment of Alzheimer’s disease, as discussed above in incorporated herein by reference.
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of XU et al. is that XU et al. do not expressly teach the inclusion of an active for treating Alzheimer’s Disease comprising pyrrolidone dithiocarbamate and/or diethyldithiocarbamate.
Zaki et al. teaches Pyrrolidine dithiocarbamate (PDTC) protects against scopolamine-induced cognitive impairment in rats, and the potential of the same for treating Alzheimer’s disease (see whole document). And Dvorak et al. teaches PDTC and diethyldithiocarbamate (DDTC) as having the same chemistry, and particularly as inhibitors of nuclear factor-kB (NF-kB) signaling cascade (see whole document).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat Alzheimer’s disease using a dual targeting nanocarrier such as the PDA-SEG taught by XU, because XU teaches treating cancer of which brain cancer is known using dual targeting nanocarriers, as suggested by Ying et al. and Riganti et al., where Riganti et al. clearly suggests the dual brain targeting approach for both brain cancer and Alzheimer’s disease, the targeting species glutathione and scopine both having been known to delivery drugs across the BBB, as suggested by Salem et al. (teaching scopine and glutathione), and Wang et al. (teaching scopine), and further to utilize a known drug for treating Alzheimer’s disease such as indomethacin, as suggested by Bernardi et al. as useful for the same; and further to include PDTC and/or DDTC as a suitable Alzheimer’s therapeutic agent, as suggested by Zaki et al. and Dvorak et al.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because XU teaches nanocarriers for the treatment of cancer (front page, [0009]) for intravenous delivery ([0052]), including methods of making the same, and it would have required no more than an ordinary level of skill in the art to covalently attach (conjugate) glutathione, scopine and an active agent such as indomethacin to the polymers described therein. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over XU (US 2014/0011760; published January, 2014) in view of Ying et al.; Riganti et al.; Salem et al.; Wang et al. and Bernardi et al. as applied to claims 1, 3-7, 11 and 14 above, and further in view of Anekonda (“Resveratrol—A boon for treating Alzheimer's disease?” 2006, Brain Research Reviews, Vol. 52, pp. 316-326).
Applicants Claims
Applicant claims a method for delivering a biologically active agent across the blood brain barrier of a subject diagnosed with Alzheimer’s Disease, as discussed above. Applicant further claims the biologically active agent comprises resveratrol (instant claim 10).
Determination of the scope
and content of the prior art (MPEP 2141.01)
XU teaches novel polymers and the preparation of nanogel drug cocktails, as discussed above and incorporated herein by reference.
Ying et al. teaches liposomes with the targeting agent p-aminophenyl-α-D-mannopyroside (MAN) and transferrin (TF), as discussed above and incorporated herein by reference.
Riganti et al. teaches the role of ABC transporters in controlling drug penetration into the brain parenchyma, the rationale for using nanoparticle- and liposome-based strategies to increase drug delivery across the BBB, as discussed above and incorporated herein by reference.
Salem et al. teaches Targeting brain cells with glutathione-modulated nanoliposomes, as discussed above and incorporated herein by reference.
Wang et al. teaches scopine as novel brain-targeting moiety, as discussed above and incorporated herein by reference.
Bernardi et al. teaches indomethacin-loaded lipid-core nanocapsules for treatment of Alzheimer’s disease, as discussed above in incorporated herein by reference.
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of XU et al. is that XU et al. do not expressly teach the inclusion of an active for treating Alzheimer’s Disease comprising resveratrol.
Anekonda teaches resveratrol as a potential treatment for Alzheimer’s disease (see whole document), and particularly concludes that: “The efficacy of resveratrol in treating AD pathology depends on the extent to which resveratrol metabolites become bioavailable and influence both sirtuin-dependent and -independent signaling pathways in humans, and also depends on the next generation of clinical testing and research that will need to study the effects of resveratrol on a large number of human subjects.” (p. 323, §10).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat Alzheimer’s disease using a dual targeting nanocarrier such as the PDA-SEG taught by XU, because XU teaches treating cancer of which brain cancer is known using dual targeting nanocarriers, as suggested by Ying et al. and Riganti et al., where Riganti et al. clearly suggests the dual brain targeting approach for both brain cancer and Alzheimer’s disease, the targeting species glutathione and scopine both having been known to delivery drugs across the BBB, as suggested by Salem et al. (teaching scopine and glutathione), and Wang et al. (teaching scopine), and further to utilize a known drug for treating Alzheimer’s disease such as indomethacin, as suggested by Bernardi et al. as useful for the same; and further to include resveratrol as a suitable Alzheimer’s therapeutic agent, as suggested by Anekonda.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because XU teaches nanocarriers for the treatment of cancer (front page, [0009]) for intravenous delivery ([0052]), including methods of making the same, and it would have required no more than an ordinary level of skill in the art to covalently attach (conjugate) glutathione, scopine and an active agent such as indomethacin to the polymers described therein. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over XU (US 2014/0011760; published January, 2014) in view of Ying et al.; Riganti et al.; Salem et al.; Wang et al. and Bernardi et al. as applied to claims 1, 3-7, 11 and 14 above, and further in view of Mishra et al. (The effect of curcumin (turmeric) on Alzheimer's disease: An overview,” 2008; Annals of Indian Academy of Neurology Vol. 11, No. 1, pp. 13-19).
Applicants Claims
Applicant claims a method for delivering a biologically active agent across the blood brain barrier of a subject diagnosed with Alzheimer’s Disease, as discussed above. Applicant further claims the biologically active agent comprises curcumin (instant claim 12).
Determination of the scope
and content of the prior art (MPEP 2141.01)
XU teaches novel polymers and the preparation of nanogel drug cocktails, as discussed above and incorporated herein by reference.
Ying et al. teaches liposomes with the targeting agent p-aminophenyl-α-D-mannopyroside (MAN) and transferrin (TF), as discussed above and incorporated herein by reference.
Riganti et al. teaches the role of ABC transporters in controlling drug penetration into the brain parenchyma, the rationale for using nanoparticle- and liposome-based strategies to increase drug delivery across the BBB, as discussed above and incorporated herein by reference.
Salem et al. teaches Targeting brain cells with glutathione-modulated nanoliposomes, as discussed above and incorporated herein by reference.
Wang et al. teaches scopine as novel brain-targeting moiety, as discussed above and incorporated herein by reference.
Bernardi et al. teaches indomethacin-loaded lipid-core nanocapsules for treatment of Alzheimer’s disease, as discussed above in incorporated herein by reference.
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of XU et al. is that XU et al. do not expressly teach the inclusion of an active for treating Alzheimer’s Disease comprising curcumin.
Mishra et al. teaches the treatment of Alzheimer’s disease using curcumin (see whole document), and particularly that “Due to various effects of curcumin, such as decreased Beta-amyloid plaques, delayed degradation of neurons, metal-chelation, anti-inflammatory, antioxidant and decreased microglia formation, the overall memory in patients with AD has improved.” (abstract, lines 7-9)
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat Alzheimer’s disease using a dual targeting nanocarrier such as the PDA-SEG taught by XU, because XU teaches treating cancer of which brain cancer is known using dual targeting nanocarriers, as suggested by Ying et al. and Riganti et al., where Riganti et al. clearly suggests the dual brain targeting approach for both brain cancer and Alzheimer’s disease, the targeting species glutathione and scopine both having been known to delivery drugs across the BBB, as suggested by Salem et al. (teaching scopine and glutathione), and Wang et al. (teaching scopine), and further to utilize a known drug for treating Alzheimer’s disease such as indomethacin, as suggested by Bernardi et al. as useful for the same; and further to include curcumin as a suitable Alzheimer’s therapeutic agent, as suggested by Mishra et al.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because XU teaches nanocarriers for the treatment of cancer (front page, [0009]) for intravenous delivery ([0052]), including methods of making the same, and it would have required no more than an ordinary level of skill in the art to covalently attach (conjugate) glutathione, scopine and an active agent such as indomethacin to the polymers described therein. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over XU (US 2014/0011760; published January, 2014) in view of Ying et al.; Riganti et al.; Salem et al.; Wang et al. and Bernardi et al. as applied to claims 1, 3-7, 11 and 14 above, and further in view of Imbimbo (“The potential role of non-steroidal antiinflammatory drugs in treating Alzheimer’s disease,” 2005, Expert Opinion on Investigational Drugs, Vol. 13, No. 11, pp. 1469-1481).
Applicants Claims
Applicant claims a method for delivering a biologically active agent across the blood brain barrier of a subject diagnosed with Alzheimer’s Disease, as discussed above. Applicant further claims the biologically active agent comprises sulindac (instant claim 13).
Determination of the scope
and content of the prior art (MPEP 2141.01)
XU teaches novel polymers and the preparation of nanogel drug cocktails, as discussed above and incorporated herein by reference.
Ying et al. teaches liposomes with the targeting agent p-aminophenyl-α-D-mannopyroside (MAN) and transferrin (TF), as discussed above and incorporated herein by reference.
Riganti et al. teaches the role of ABC transporters in controlling drug penetration into the brain parenchyma, the rationale for using nanoparticle- and liposome-based strategies to increase drug delivery across the BBB, as discussed above and incorporated herein by reference.
Salem et al. teaches Targeting brain cells with glutathione-modulated nanoliposomes, as discussed above and incorporated herein by reference.
Wang et al. teaches scopine as novel brain-targeting moiety, as discussed above and incorporated herein by reference.
Bernardi et al. teaches indomethacin-loaded lipid-core nanocapsules for treatment of Alzheimer’s disease, as discussed above in incorporated herein by reference.
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of XU et al. is that XU et al. do not expressly teach the inclusion of an active for treating Alzheimer’s Disease comprising sulindac.
Imbimbo teaches the potential role of non-steroidal anti-inflammatory drugs in treating Alzheimer’s disease (see whole document), and particularly that “The first report linking the protective role of NSAIDs against Alzheimer’s disease with their ability to lower amyloid-β secretion was published in 2001 [30]. In this pioneering work, selected NSAIDs (ibuprofen, indomethacin and sulindac sulfide) were shown to preferentially inhibit, in a dose-dependent manner, the secretion of the Aβ42 peptide in a variety of cultured cells (Figure 1).” (p. 1472, col. 2, lines 1-7).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat Alzheimer’s disease using a dual targeting nanocarrier such as the PDA-SEG taught by XU, because XU teaches treating cancer of which brain cancer is known using dual targeting nanocarriers, as suggested by Ying et al. and Riganti et al., where Riganti et al. clearly suggests the dual brain targeting approach for both brain cancer and Alzheimer’s disease, the targeting species glutathione and scopine both having been known to delivery drugs across the BBB, as suggested by Salem et al. (teaching scopine and glutathione), and Wang et al. (teaching scopine), and further to utilize a known drug for treating Alzheimer’s disease such as indomethacin, as suggested by Bernardi et al. as useful for the same; and further to include sulindac as a suitable Alzheimer’s therapeutic agent, as suggested by Imbimbo.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because XU teaches nanocarriers for the treatment of cancer (front page, [0009]) for intravenous delivery ([0052]), including methods of making the same, and it would have required no more than an ordinary level of skill in the art to covalently attach (conjugate) glutathione, scopine and an active agent such as indomethacin to the polymers described therein. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
Response to Arguments:
Applicant's arguments filed 11/12/2025 have been fully considered but they are not persuasive.
Applicant argues that: “As argued previously, and acknowledged in the Office Action, Xu fails to disclose or suggest that following the crossing of the blood brain barrier, disulfide bonds of the first, second and third copolymer are degraded, thereby releasing the biologically active compound and detaching the first and second blood brain barrier transporters from the nanoparticle in the brain of the subject, as set forth in amended independent claim 1.” (p. 8, 2nd paragraph).
In response the examiner argues that “Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention.” (MPEP §2145(II). In the instant case the prior art XU clearly teaches that: “Since both ND and NCPD were made of the same polymer and fabricated from the same assembly method (except the loaded drugs), for simplification we used ND nano gel as a model to investigate the NCPD nanogel response to the stimuli of both pH and redox potential and its cellular uptake and intracellular trafficking. To validate the pH responsive property of the nanogel, we carried out the drug release kinetic measurement at both pH 7.4 and 5.5 to mimic the physiological and lysosomal pH. […] However, there was no significant increase of drug released in the acetic buffer containing 10 mM DTT, which we think is due to both acidic pH and redox potential resulted in same side chain cleavage regardless the breaking points. To further investigate the intracellular behavior of the redox sensitive nanogel, we added TCEP to simulate the intracellular elevated glutathione condition. FIG. 28 showed that ND nanogel quickly increased its size from 113 nm to 262 nm after 5 hr incubation in PBS (pH 7.4 containing 1 mM of TCEP). Transmission electron microscopy also proved the enlargement of the nanogel (FIG. 2C). Since the ND nanoparticle is negatively charged, the cleavage of disulfide bonds will result in the swelling of the nanogel due to the repulsion force between charged polymer blocks. We expect the redox responsive swelling of the nano gel will break up the lysosome membrane and facilitate its trafficking to nuclei.” [emphasis added]([0066]). Fairly, suggesting the disclosed degradation “As utilized herein, an acidic-sensitive bond can generally refer to a bond that will degrade or otherwise break in an environment of about pH 6.8 or less, for instance about pH 4 to about pH 6.8, and will be more stable in an environment at higher pH (e.g., about 7 or higher). A redox potential-sensitive bond can generally refer to a bond that will degrade in an environment having a redox potential equal to that of a glutathione concentration of from about 0.1 mM to about 10 mM).” ([0024]). And that: “The ligands can be bonded to the nanoparticle by environmentally sensitive linkages that can degrade in an environment including acidic pH and/or high redox potential. As such, the nanoparticles can circulate in a subject's system, pass the blood brain barrier through the targeting provided by the two (or more) functional ligands, and then release their payload following entry into the brain environment due to the sensitivity of the ligand attachment bonds to the environment of the blood brain barrier lysosome and/or the nervous system.” ([0022]).
Applicant further argues that: “Riganti and Ying discuss dual targeting in the context of brain cancers and general BBB passage, but do not provide data or teaching specific to neurodegenerative disease or neuronal uptake. For instance, Riganti merely surveys general BBB strategies without teaching or suggesting the claimed dual-ligand Alzheimer's system. As such, Applicant respectfully submits that there is no proper rationale as to why a skilled artisan would have been motivated to combine a cancer specific nanogel with Ying and/or Riganti's general BBB commentary to produce Applicant's dual-targeted, Alzheimer's nanocarrier. The skilled artisan would recognize that cancer nanocarriers rely on the EPR effect and tumor receptor overexpression for uptake, while the Alzheimer's brain presents a tight-junction-sealed BBB and neuronal targets with entirely different surface receptors.” (p. 8, 3rd paragraph). And that: “the microenvironmental triggers (pH, redox potential) in the Alzheimer's brain differ markedly from those in tumors, so the release mechanisms of Xu's nanogel would not translate predictably. Accordingly, there would have been no reasonable expectation of success that the tumor-specific system of Xu could be adapted to cross an intact BBB and deliver anti-Alzheimer's agents. The Office Action's rationale thus rests on impermissible hindsight reconstruction […].” (paragraph bridging pp. 8-12).
In response the examiner argues that the instantly rejected claims simply require systemically administering the claimed nanoparticles which are identical to those of XU but substituted with different blood brain barrier (BBB) crossing ligands, and agents to be delivered to the Brain of a subject diagnosed with Alzheimer’s Disease. Crossing the BBB to delivery a drug to the brain of a subject is the same in brain cancer and other brain diseases such as Alzheimer’s disease. Additionally, Applicants argument of a distinction between the brain of a cancer patient and the brain of an Alzheimer’s patient does not appear to be supported by evidence of record. Indeed, XU teaches the same release mechanism (pH + redox triggered release) and does not expressly teach delivery of their nanoparticles across the BBB, clearly suggesting that Applicants argument is a difference without a distinction of the claimed invention. And further give that XU teaches the same release mechanism (pH + redox triggered release) provides a clear basis for a reasonable expectation of success that including a BBB crossing ligand (i.e. dual-targeting) nanoparticles would have resulted in the same release mechanism in the patients brain.
Applicant further argues that: “Additionally, Salem and Wang are cited for teaching scopine and glutathione, and Bernardi is cited for its contemplation of treating Alzheimer's disease with indomethacin. Salem teaches improved small-molecule BBB penetration via a single glutathione ligand, not a dual-targeted polymeric nanoparticle. Salem merely mentions scopine in a laundry list of targeting moieties. Wang teaches that scopine's BBB transport properties increase the brain uptake of chlorambucil, not its use for neuronal delivery or combination with GSH. Bernardi teaches indomethacin lipid nanocapsules for Alzheimer's models. Applicant respectfully submits that the suggestion that one could merely substitute an anti-Alzheimer's agent, such as indomethacin, into Xu's system presupposes that the same carrier architecture and ligand combination would traverse the BBB and target neuronal tissues, which is an assumption unsupported by the art. The only way to conceive of merging XU's cancer nanogel with Salem's glutathione, Wang's scopine, and Bernardi's indomethacin is with the benefit of Applicant's Specification, which explicitly teaches that the dual-ligand configuration yields unexpectedly improved BBB penetration and Alzheimer's therapeutic effect. Without Applicant's disclosure, a skilled artisan would have no reason to predict that these unrelated elements could be successfully combined. Thus, the Office Action's rationale rests on impermissible hindsight reconstruction […].” (p. 9, 2nd paragraph).
In response the examiner argues that, based on the cited combination of references, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat Alzheimer’s disease using a dual targeting nanocarrier such as the PDA-SEG taught by XU, because XU teaches treating cancer of which brain cancer is known using dual targeting nanocarriers, as suggested by Ying et al. and Riganti et al., where Riganti et al. clearly suggests the dual brain targeting approach for both brain cancer and Alzheimer’s disease, the targeting species glutathione and scopine both having been known to delivery drugs across the BBB, as suggested by Salem et al. (teaching scopine and glutathione), and Wang et al. (teaching scopine), and further to utilize a known drug for treating Alzheimer’s disease such as indomethacin, as suggested by Bernardi et al. as useful for the same. 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).
Applicant further argues that: “Surprisingly, because of the detachment of the transporter in the brain, in the Present Application, the nanoparticle, together with biologically active compounds, will be retained in the brain after being transported from the bloodstream into the brain, thus yielding a much higher efficiency than other existing systems in delivering biologically active compounds into the brain. FIG. 5 of the Present Application (reproduced in color below) depicts fluorescence images of tissues collected from the LPS induced inflammatory mouse model after receiving NAC treatment. As can be seen in FIG. 5, the NAC-DTDRN treated mouse exhibited a quenched fluorescence signal in the brain, which illustrates the protection of NAC-DTDRN after it penetrated the blood brain barrier. Additionally, fluorescence images of the brain sections collected from the LPS induced inflammatory mouse model after receiving NAC treatment are shown in FIG. 6 of the Present Application (reproduced in color below). The diminished red fluorescence dots in the brain of NAC-DTDRN treated mouse illustrates that the NAC-DTDRN can effectively reduce the brain reactive oxygen species (ROS) levels.” (paragraph bridging pp. 9-10).
In response the examiner argues that MPEP §716.02 – “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected.” and the burden is on Applicant to establish the results are unexpected and significant “The evidence relied upon should establish ‘that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.’” (§716.02b). And any unexpected results must be commensurate in scope with the claimed invention – “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.’” (§716.02d) And any comparative data should be with the closest prior art or closer (§716.02e). In the instant case the data shown includes: (1) “Control NP”, (2) “Scopine NP”, (3) “GHS NP” and (4) “Scopine/GHS NP” (Table 1, on with the NAC loaded DTDRN is based). Additionally, NAC active is limited in claim 2, the PDA polymer is 2-(pyridin-2-yldisulfanyl)ethyl acrylate (PDA) – (instant claim 6). Therefore, the claims are not commensurate with any results shown as they are broader than the Examples of the instant Specification and Applicant has provided no evidence that they should be supportive of the claimed genus (copolymers, biologically active compound(s), and BBB-transporters).
Applicant further argues that “In order to combine the references as suggested, one of skill in the art would need proper rationale to combine a biologically active agent, as required in amended independent claim 1, and conjugate it to the PDA components of Xu. Moreover, one would need to make this change while ignoring the fact that the nanogels of Xu actually include PEG components that could be used for BBB transporter conjugation, as taught by the references. No proper rationale has been provided as to why one of skill in the art would simply ignore the teachings of the references and make this further modification. A further modification that, based upon the teaching of the references when read as a whole, as required, is neither suggested nor necessary. Clearly, the suggested combination and further modification has been obtained only through hindsight reconstruction from the Applicant's Specification, which is improper.” (p. 11, 1st paragraph).
The examiner maintains that XU teaches novel polymers and the preparation of nanogel drug cocktails specifically for drug delivery, and brain targeting for the treatment of Alzheimer’s would have been prima facie obvious for the treatment of the same. And the active ingredients were know as suitable for treatment of Alzheimer’s disease. As discussed above, it is clear that XU teaches cleavage of the disulfide bonds in “the physiological and lysosomal pH” and under “intracellular elevated glutathione condition”, therefore it would have been prima facie obvious that under those same conditions upon administration the first (Scopine) and second (glutathione) blood brain barrier transporters would have inherently been subjected to cleavage (i.e. detaching the first and second blood brain barrier transporters from the nanoparticle in the brain of the subject). The examiner maintains that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat Alzheimer’s disease using a dual targeting nanocarrier such as the PDA-SEG taught by XU, because XU teaches treating cancer of which brain cancer is known using dual targeting nanocarriers, as suggested by Ying et al. and Riganti et al., where Riganti et al. clearly suggests the dual brain targeting approach for both brain cancer and Alzheimer’s disease, the targeting species glutathione and scopine both having been known to delivery drugs across the BBB, as suggested by Salem et al. (teaching scopine and glutathione), and Wang et al. (teaching scopine), and further to utilize a known drug for treating Alzheimer’s disease such as indomethacin, as suggested by Bernardi et al. as useful for the same.
Conclusion
Claims 1-14 are pending and have been examined on the merits. The specification is objected to and claims 1-14 are rejected under 35 U.S.C. 103. No claims allowed at this time.
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 IVAN A GREENE whose telephone number is (571)270-5868. The examiner can normally be reached M-F, 8-5 PM PST.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619