DETAILED ACTION
Status of the Claims
Claims 128-145 are pending in the instant application. Claims 130-143 have been withdrawn based upon Restriction/Election. Claims 128, 129, 144 and 145 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All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.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 U.S. effective filing date has been determined to be 11/23/2015, the filing date of the U.S. Provisional Application No. 61/258,773. Support for bolaamphiphiles: GLH-64(a), GLH-64(b), GLH-64(c), GLH-64(d), and GLH-64(e) (‘773: p. 136, [00575]) is not found in any prior filed in priority document
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 128, 129, 144 and 145 remain rejected under 35 U.S.C. 103 as being unpatentable over LINDER (US 2012/0164072; published 06/02/2012) in view of Dakwar et al. (“Delivery of proteins to the brain by bolaamphiphilic nano-sized vesicles,” 09-JAN-2012; ELSEVIER; Journal of Controlled Release, Vol. 160, pp. 315-321) and GROSS (U.S. 5,981,743; published November, 1999).
Applicants Claims
Applicant claims a pharmaceutical composition which comprises nanovesicles which comprise (1) the bolaamphiphiles GLH-19 and GLH-20 in a molar ratio of 2:1; (2) 1-10 molar percent based on total bolaamphiphiles of one or more bolaamphiphiles selected from the group consisting of GLH-64a, GLH-64b, GLH-64c, GLH-64d, and GLH-64e; and (3) a stabilizer which is cholesterol hemisuccinate and cholesterol (instant claim 128).
Determination of the scope
and content of the prior art (MPEP 2141.01)
LINDER teaches nano-sized particles comprising at least one multi-headed amphiphilic compound and a biologically active agent for drug delivery (see whole document), and particularly “bolaamphiphiles” which are double-headed amphiphiles ([0023]). LINDER teaches bolaamphiphiles comprise cationic head groups and form nano-sized vesicles in the presence of active agent solutes selected from peptides, proteins, polynucleotides and non-polymeric molecules ([0023]). LINDER teaches that “when molecules with anionic carboxylic groups such as cholesterol hemisuccinate were mixed with cationic bolaamphiphiles, stable vesicles were formed wherein cholesterol hemisuccinate was shown to be taken up in the outer surface of the vesicles.” ([0024])(instant claim 128, “a stabilizer is cholesterol hemisuccinate”).
LINDER teaches that “The present inventors further found that use of amphiphiles with cationic headgroups such as choline ester headgroups, improved penetration of the vesicles made therefrom through biological barriers. Penetration of nanoparticles via the BBB was shown to be accelerated by providing them with cationic surface groups.” [emphasis added]([0027]).
LINDER teaches that: “The present inventors also found that attaching certain additives such as chitosan, chitosan derivatives and polyamines to the nanoparticles surface enhanced penetration through the intestinal tract as well as other biological barriers.” ([0029])
LINDER further teaches that “In particular embodiments, the nano-sized particles comprise a mix of bolaamphiphiles with different headgroups. In more particular embodiments, these bolaamphiphiles comprise different alkyl choline derivatives.” ([0174]). And further that “In a specific embodiment, the nanoparticle of the invention comprise a mixture of Derivative 1 and Derivative 4, preferably in the ratio 2:1, respectively. These bolaamphiphilic derivatives differ in the way the acetylcholine head group is linked to the aliphatic chain. Nanoparticles comprising said mixture loaded with a biologically active agent such as enkephalin released the encapsulated material more slowly compared to nanoparticle based only on Derivative 4, due to the [much] less efficient cleavage of the acetylcholine group of Derivative 1.” ([0175]). LINDER teaches Derivative 1 is shown in Scheme 4 ([0256]) and Derivative 4 is shown in scheme 5 ([0314]) which are depicted as follows:
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472
727
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where Derivative 1 is consistent with GLH-19 and Derivative 4 is consistent with GLH-20 as disclosed in Table 1 of the instant specification:
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173
805
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LINDER further teaches Example 28 combining Derivative 1 and Derivative 4 and states “that by combining different bolaamphiphiles, the delivery and release of active agents such as peptides proteins and polynucleotides can be optimized.” ([0386])(instant claim 1, GLH-19 and GLH-20).
LINDER teaches that: “In certain embodiments, the nanoparticles of the invention comprise mixtures of different multi-headed amphiphiles, and mixtures of at least one multi-headed amphiphile and at least one single headed amphiphile, which form vesicles with homogeneous or heterogeneous membrane structure. In any case, according to the invention, at least one of the multi-headed amphiphiles is a bolaamphiphile.” ([0173]). And that: “In particular embodiments, the nano-sized particles comprise a mix of bolaamphiphiles with different head groups. In more particular embodiments, these bolaamphiphiles comprise different alkyl choline derivatives.” ([0174]). And further that: “In a specific embodiment, the nanoparticle of the invention comprise a mixture of Derivative 1 and Derivative 4, preferably in the ratio 2:1, respectively.” [emphasis added]([0175] & [0333])(instant claim 1, “nanovesicles which comprise (1) the bolaamphiphiles GLH-19 and GLH-20 in a molar ratio of 2:1” where Derivative 1 = GLH-19 and Derivative 4 = GLH-20). LINDER teaches that: “The following method was typically used for obtaining nanoparticles with additives. Unless mentioned otherwise, the molar ratio of bolaamphiphile:cholesteryl hemisuccinate:cholesterol was 2:1:1, respectively.” ([0231])(instant claim 144).
LINDER teaches that the nano-sized particles are most often in the form of vesicles or liposomes formed from multi-headed amphiphiles having a core and a membrane surrounding the core, made at least in part from these amphiphiles ([0035]).
LINDER teaches bioactive agents useful for delivery by the nano-particles of their invention include glial cell line derived neurotrophic factor (GDNF), particularly for the treatment of Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and for the treatment of spinal cord injuries ([0179]-[0181]) (instant claim 129).
LINDER teaches that “bolaamphiphiles comprising selectively cleavable headgroups bearing net ionic charge, preferably cationic headgroups, are advantageous according to the invention for three main reasons: (a) they form vesicles with good circulatory survival and ability of penetrating, intact, through biological barriers such as the blood-brain barrier (BBB), for example via transcytosis; (b) they provide vesicles with a selective disruption mechanism in the CNS, which enables the release of the encapsulated material in the brain in a controlled manner; and (c) they exhibit excellent encapsulation efficiency with anionic molecules such as peptides, proteins and nucleotides, via both complexation and encapsulation.” ([0165]). And that “For the purpose of administering drugs to the brain, the nanoparticles of the invention may contain, besides the aforementioned selectively cleavable headgroups, ligands of specific receptors at the target site, presented as functional groups or pendants on the surface of the nanoparticles for targeting purposes, and/or ligands and surface groups which increase permeability through the BBB.” ([0197]).
LINDER further teaches that "Other additives used according to the invention for improving brain drug delivery, include modified proteins or antibodies that undergo absorptive-mediated or receptor-mediated transcytosis through the blood-brain barrier, such as bradykinin B2 agonist RMP-7 or monoclonal antibody to the transferrin receptor. Other ligands are monosaccharides such as glucose, mannose, ascorbic acid and derivatives thereof, for example, glucose derivatives which use the glucose transporters GLUT-1 and paminophenyl-alpha-mannopyranoside." [ emphasis added]([0200]).
LINDER teaches producing a bolaamphiphile species 1,10-Decane Diricinoleate by using ricinoleic acid and 1,10-decanediol catalyzed by lipase acrylic resin from candida Antarctica in toluene ([0281]) to produce the symmetric bolaamphiphilic molecule of precursor 9 (n = 10).
LINDER teaches a similar procedure for the production of Decane Divernolate, that is, by reacting vernolic acid with 1,10-decanediol catalyzed by lipase acrylic resin, a species that is subsequently reacted to form Decane Divernolate Diglutaric acid ([00256]-[0259]; Example 4). Thus, the prior art (LINDER) fairly suggests reacting precursor 9 with glutaric acid to form Decane Diricinoleate Diglutaric acid (instant specification p. 18).
LINDER teaches that: “Bolaamphiphiles can be classified as either symmetrical or asymmetrical with respect to their headgroups. In symmetric bolaamphiphiles, both headgroups are the same whereas in asymmetrical bolaamphiphiles the headgroups are different with respect to their structure, electric charge and/or bulkiness.” ([0166]). And further that: “In certain embodiments, the bolaamphiphiles are asymmetric bolaamphiphiles that have two headgroups of different size or bulkiness. The difference in headgroups size may vary from very small, intermediate, to a very large difference, and can be optimized to maximize amphiphile packing and thus vesicle stability for a bolaamphiphile with a given total size and a given span between the two headgroups on the aliphatic chain. Optimized size calculations for bolaamphiphiles with different headgroups are well known in the art.” ([0167]).
LINDER further teaches that “Additives which enhance transport across membranes of the intestinal tract are also encompassed by the present invention. Such additives include, but are not limited to, chitosan (CS) and derivatives of chitosan […].”([0201]). LINDER teaches that: “The present inventors have shown that CS and particularly a novel CS derivative vernolyl-chitosan, a conjugate of CS and vernolic acid, is a very efficient penetrant of the BBB […].” [emphasis added]([0203]).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of LINDER is that LINDER does not expressly teach a bolaamphiphilic compound formed by reacting Decane Diricinoleate Diglutaric acid with a mannose sugar ligand to form GLH-64a, and thus produce a pharmaceutical composition nanovesicle in combination with GLH-19 and/or GLH-20 including the same.
LINDER teaches Synthesis of Vernoyl Chitosan (p. 15, Example 1) including the Preparation of Vernolic Acid N-Hydroxysuccinimide (Ver-NHS)([00242]-[0245]), as well as the synthesis of vernolyl glycol chitosan (p. 16, Example 1; p. 28, Scheme 1). LINDER teaches the synthesis of the asymmetric bolaamphiphile Derivative 2 including an acetylcholine head group (pp. 17, Example 5). Therefore it would have been within the ordinary level of skill in the art to produce an asymmetric bolaamphiphilic compound including a first head group of acetylcholine and a second head group of chitosan. LINDER teaching the motivation to do so includes “(a) they form vesicles with good circulatory survival and ability of penetrating, intact, through biological barriers such as the blood-brain barrier (BBB), for example via transcytosis; (b) they provide vesicles with a selective disruption mechanism in the CNS, which enables the release of the encapsulated material in the brain in a controlled manner; and (c) they exhibit excellent encapsulation efficiency with anionic molecules such as peptides, proteins and nucleotides, via both complexation and encapsulation.” ([0165]). Thus by using the chemistry described within LINDER one of ordinary skill in the art could attach chitosan to one of the heads of the bolaamphiphile producing the claimed/elected compound. Reason to make such a modification would be to enhance permeably of the drug delivery system through biological barriers such as the BBB, along with the potential for increasing encapsulation efficiency with anionic molecules.
Dakwar et al. teaches that: “In the present study we investigated if such bolaamphiphilic vesicles are also capable of delivering proteins across biological barriers, particularly through the BBB.” (p. 316, col. 1, 2nd paragraph). Dakwar et al. further teaches that: “We also synthesized chitosan (CS)-vernolic acid conjugate (Fig. 2), which provides the vesicles with CS surface pendants to enhance vesicle transport through biological barriers.” (p. 316, §2.1, 2nd paragraph; Figure 2). Dakwar et al. teaches that “These results show that cationic bolaamphiphilic vesicles with ACh head groups are capable of delivering proteins across biological barriers, such as the cell membrane and the blood-brain barrier (BBB). Brain ChE activity destabilizes the vesicles and releases the encapsulated protein, enabling its accumulation in the brain.” (see whole document, particularly the last 4 lines of abstract).
GROSS teaches oligomers composed of carbohydrate headgroups and methods for making the same (see whole document). GROSS teaches that "Primary hydroxyl group," as used herein, means a hydroxyl group bound to a carbon atom that has two hydrogen atoms bound to it, and "Secondary hydroxyl group," as used herein, means a hydroxyl group bound to a carbon that has one hydrogen atom bound to it; and "Carbohydrate head group," as used herein, means a carbohydrate in which at least one of the primary hydroxyl groups is linked to an end group of an oligomer chain ( col. 2, lines 37-46). GROSS teaches that "In one aspect, the invention features an oligomer that includes an oligomer chain and a carbohydrate head group that has a primary hydroxyl group; the oligomer chain is linked to the primary hydroxyl group. The oligomer can contain one carbohydrate head group[ ... ]." ( col. 1, lines 55-60). GROSS teaches that examples of carbohydrates include mannose, among others (col. 30-45). GROSS teaches that the enzymes useful include candida Antarctica (NOVOZYME 435™) ( col. 5, lines 9-10).
The structure of the compound GLG-64a-e are described as “3)several types of GLH-64 (GLH-64a-e), a bola family with mannose head groups that target the vesicles to mannose receptors.” (p. 136, [00575]).
LINDER teaches that: “The symmetric bolaamphiphile Derivative 5, which bears two glutamic acid head groups, can be used as an additive in the formation of nanoparticles comprising asymmetric bolaamphiphiles such as Derivative 3 and or symmetric Derivative 4, and constitutes only about 10% of the total amphiphiles' mass. Addition of this bolaamphiphile resulted in nanoparticles having improved blood circulatory.” ([0273], Example 7; p. 30, Derivative 3; p. 29, Derivative 4). And that: “The synthesis of symmetric and asymmetric bolaamphiphilic compounds from castor oil based on ricinoleic acid or methyl ricinolate with the acetylcholine head group attached through the nitrogen atom of acetyl choline is as follows.” ([0280], Example 8; p. 21, top structure).
LINDER claims: “A nano-sized particle comprising at least one multi-headed amphiphilic compound, in which at least one head group of said multi-headed amphiphilic compound is selectively cleavable or contains a selectively cleavable group, and at least one biologically active agent, which is both encapsulated within the nano-particle and non-covalently associated thereto.” (claim 1). And that: “The nano-sized particle according to claim 1, wherein at least one of the headgroups of said multi-headed amphiphilic compound serve as substrates to enzymes at a target site in a biological environment, enhance transport of the nano-sized particle through biological barriers and/or stabilize the vesicular structure of the nano-sized particle.” (claim 11). And further that: “The nano-sized particle according to claim 11, wherein said headgroup is selected from: […] (iv) saccharides such as glucose, mannose […].” (claim 15).
It would have been prima facie obvious to synthesize a bola including a backbone of Decane Diricinoleate (LINDER – Examples 7-8 and claims 1, 11 & 15(iv); Dakwar et al. – backbone of GLH-19 and GLH-20; ), as with the bolas GLH-19 and GLH-20, and utilize the headgroup mannose attached to the primary hydroxyl group to produce GLH-64a.
GROSS teaches that "In addition, the oligomers can also be used to form biocompatible micelles. [ ... ] These micelles can be used for the controlled release of hydrophobic low molecular weight drugs. The drugs are initially contained in the hydrophobic interior of the micelle, then slowly diffuse out of the micelles in vivo." (col. 6, lines 45-55).
Regarding the amount of the bolaamphiphile GLH-64(a-e) being 1 to 10 molar percent, the examiner takes the position that the prior art clearly suggest including targeting moieties such as for brain targeting, therefore one of ordinary skill in the art would have likely arrived at the same amount of the GLH-64 family bolaamphiphile in the same amount base on optimization for the same intended use (MPEP §2144.05-II & 2144.07)(LINDER, [0167]). Additionally, the inclusion of mixtures of bolaamphiphile molecules to form the vesicles including GLH-19 and GLH-20 in a molar ratio of 2:1 (instant claims 128 & 145), and a molar ratio of bolaamphiphile(s) : cholesterol : cholesteryl hemisuccinate of 2:1:1 (instant claim 144) is clearly suggested by the combination of prior art (LINDER, [0351]; Dakwar et al., p. 316, §2.4).
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 produce a bolaamphiphilic vesicles are also capable of delivering proteins across biological barriers, particularly through the BBB, as suggested by LINDER and Dakwar et al, including GLH-19 and GLH-20 in a molar ratio of 2:1, as taught by LINDER and Dakwar et al., and further to synthesize a bola including a backbone of Decane Diricinoleate (LINDER – Example 8 and claims 1, 11 & 15(iv); Dakwar et al. – backbone of GLH-19 and GLH-20; ), as with the bolas GLH-19 and GLH-20, and utilize the headgroup mannose attached to the primary hydroxyl group to produce GLH-64a, and to produce bolaamphiphilic vesicles including the same as suggested by Dakwar et al. and LINDER brain delivery (LINDER [0200], and Dakwar et al. – see whole document).
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 LINDER teaches the claimed bolaamphiphilic compounds GLH-19 and GLH-20, and the chemistry necessary to produce the bolaamphiphilic compound GLH-64a, particularly in view of the ordinary level of skill in the art to which the invention pertains. 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).
Response to Arguments:
Applicant's arguments filed 07/08/2026 have been fully considered but they are not persuasive.
Applicant argues that: “The Examiner dismisses these statements and relies on two Court decisions: Newell Cos. v. Kenney Mfg. Co., 864 F.2d 757, 769, 9 USPQ2d 1417, 1427 (Fed. Cir. 1988), (hereinafter Newell) and Richardson-Vicks, Inc., v. The Upjohn Co., 122 F.3d 1476, 1484, 44 USPQ2d 1181, 1187 (Fed. Cir. 1997), (hereinafter Upjohn). Applicant deems that the Examiner's reliance on these two decisions is misplaced.” And that: “The two cases are similar in that patents were granted after obviousness was overcome by evidence of surprisingly enhanced activity and success in the industry. At trials for patent infringement, both juries agreed with the two Examiners and deemed the inventions unobvious. However, the trial Courts exercised their right, as a matter of law, to ignore the juries' opinions and declared the inventions obvious. The Appeals Courts affirmed both lower court decisions. Therefore, these two decisions stand for the proposition that a trial court, as a matter of law, has the right to ignore a jury opinion as to the question of obviousness. However, what neither the trial courts nor the appeal courts have provided is any rationale or standard by which anyone can determine what level/quantity/quality of evidence of unexpected properties an applicant must provide to overcome an obviousness rejection. In the present application the Applicant has provided experimental evidence that the claimed material does not exhibit a property deemed by the Examiner to be obvious in view of the art. This is surprising and unexpected and deemed by Applicant to overcome the rejection.” (p. 5, last two paragraphs through p. 6, 1st paragraph). And that: “In view of the above, it is requested that the Examiner reconsider the data which have been provided and that he reverse his opinion. In the alternative, if the rejection is maintained, it is requested that the Examiner provide a detailed explanation why the data fail to overcome the rejection.” (p. 6, 2nd paragraph).
In response the examiner maintains that the instantly rejected claims are directed to a pharmaceutical composition which comprises nanovesicles which comprise (1) the bolaamphiphiles GLH-19 and GLH-20 in a molar ratio of 2:1; (2) 1-10 molar percent based on total bolaamphiphiles of one or more bolaamphiphiles selected from the group consisting of GLH-64a, GLH-64b, GLH-64c, GLH-64d, and GLH-64e; and (3) a stabilizer which is cholesterol hemisuccinate and cholesterol (instant claim 128).
The prior art clearly suggest GLH-19 and GLH-20 both which are suggested for delivery across the BBB - LINDER teaches that “The present inventors further found that use of amphiphiles with cationic headgroups such as choline ester headgroups, improved penetration of the vesicles made therefrom through biological barriers. Penetration of nanoparticles via the BBB was shown to be accelerated by providing them with cationic surface groups.” [emphasis added]([0027]). LINDER further teaches that: “Preferred headgroups according to the invention are those which serve as substrates to enzymes at a target site of a biological environment, e.g. hydrolytic enzymes, enhance transport of the nanoparticles through biological barriers and/or stabilize a vesicular structure of the nanoparticles. At least one of these preferred headgroups is a selectively cleavable headgroup.” ([0048]). And in paragraph [0049], such headgroups are taught to include (i) choline, and (iv) saccharides such as glucose, mannose and ascorbic acid. And while LINDER suggests that: “Other ligands are monosaccharides such as glucose, mannose, ascorbic acid and derivatives thereof, for example, glucose derivatives which use the glucose transporters GLUT-1 and p-aminophenyl-alpha-mannopyranoside.” ([0200]). The prior art clearly suggests using mannose headgroups for various reasons – “those which serve as substrates to enzymes at a target site of a biological environment, e.g. hydrolytic enzymes, enhance transport of the nanoparticles through biological barriers and/or stabilize a vesicular structure of the nanoparticles.” ([0048]).
The prior art clearly teaches the motivation to produce the claimed compositions, as discussed above. However, the further motivation of specifically targeting brain cells associated with diseases or disorders associated with the central nervous system (CNS), in particular neurological and/or neurodegenerative diseases or disorders such as Parkinson’s disease and Alzheimer’s disease, exists in the prior art as well.
The examiner cites Marzolo et al. (“Mannose Receptor Is Present in a Functional State in Rat Microglial Cells,” 1999; Journal of Neuroscience Research, Vol. 58, pp. 387-395) teaches that: “We studied the expression of the mannose receptor (ManR) in rat microglial cells. Microglial cells are the central nervous system resident macrophages, key participants of the innate immune response. ManR is a differentiation marker and a relevant glycoprotein for the phagocytic and endocytic function of macrophages. Because there is evidence suggesting that ManR could mediate some of the nonenzymatic effects of acetilcholinesterase (AchE) and the enzyme seems to be involved in Alzheimer’s disease (AD), we looked for ManR in microglia, evaluating the functionality of the receptor. […] The presence of a functional ManR in microglia opens the possibility that ManR could participate in multiple physiologic and pathologic conditions in the central nervous system (CNS), including inflammation, ischaemia, and neurodegerative diseases such as AD.” (abstract, see whole document). And that: “Microglial cells are ubiquitously distributed in the CNS and represent up to 20% of the glial population of the brain. Microglial cells have a central role in development, tissue repair, and in several neurological disorders, including trauma, brain ischaemia, Alzheimer’s disease (AD), and multiple sclerosis. They are the main immune effector cells of the CNS and the major source of several cytokines. Resting microglia activate and become macrophages after brain injury, releasing cytokines such as interleukin 1-α and tumor necrosis factor α, nitric oxide, and several inflammatory molecules.” (p. 387, col. 2, 2nd paragraph).
Minami et al. (“Selective targeting of microglia by quantum dots,” 2012, Journal of Neuroinflammation, Vol. 9, No. 22, pp. 1-13) teaching that: “Chronic inflammation is a hallmark of many neurological diseases. Microglia, innate immune cells of the CNS, become activated in response to injury and appear to have important roles in the defense against invading microbes and in wound repair. They also phagocytose dead cells and help clear misfolded protein aggregates, (Aβ) such as those formed by amyloid beta in Alzheimer’s disease (AD)” (p. 1, col. 1, lines 1-8). And that: “To determine if microglia-specific receptors, such as macrophage scavenger receptor 1 (MSR-1) and mannose receptor, mediate the uptake of QDs, we treated primary mixed cortical cultures with inhibitors against these receptors and measured QD uptake by microglia. Mannan, an inhibitor of mannose receptor, dose-dependently decreased microglial uptake of QDs (Figure 4A).” (p. 7, col. 1, §The uptake of QDs by microglia occurs through mannose and macrophage scavenger receptors). And further that: “Clathrin-mediated endocytosis occurs in all cell types. However, blocking the MSR-1 or mannose receptor with specific inhibitors or antibodies prevented the uptake of QDs, indicating that the selective targeting of QDs to microglia requires their binding to microglia specific receptors.” (p. 10, col. 2, 1st paragraph). And that: “Microglia may have roles in the pathogenesis of various CNS diseases, including multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, and amyotropic lateral sclerosis. Our finding that certain sizes of QDs selectively target microglia provides a novel platform to probe and modulate biological processes in microglia and may lay the foundation for the development of QD-based reagents that can modulate specific signaling pathways in microglia.” (p. 10, col. 2, 2nd paragraph). Minami et al. concludes that: “In conclusion, our study demonstrates that QDs can be used to specifically label and modulate microglia in primary cortical cultures and in the brain. This specificity is in part due to the selective uptake by macrophage scavenger receptors and mannose receptors present on the surface of microglia. These findings may allow for the selective imaging and delivery of therapeutic agents to microglia in a wide range of neurological disease models and, ultimately, perhaps also in the corresponding human conditions.” (p. 11, §Conclusions).
Thus, while the cited prior art (LINDER et al.) clearly suggests utilizing the mannose group ([0048]-[0049], [0200]) in compositions directed at treating “diseases or disorders selected from: (i) diseases or disorders associated with the central nervous system (CNS), in particular neurological and/or neurodegenerative diseases or disorders such as Parkinson's disease, Alzheimer's disease or multiple sclerosis; […].” ([0015]). LINDER further teaches that: “For the purpose of administering drugs to the brain, the nanoparticles of the invention may contain, besides the aforementioned selectively cleavable headgroups, ligands of specific receptors at the target site, presented as functional groups or pendants on the surface of the nanoparticles for targeting purposes, and/or ligands and surface groups which increase permeability through the BBB.” [emphasis added]([0197]). Thus, clearly suggesting including headgroups for crossing the BBB and specific targeting such as targeting the mannose receptor, as was understood in the art at the time before the claimed invention.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Regnier-Vigouroux (“The Mannose Receptor in the Brain,” 2003, ELSEVIER, International Review of Cytology, Vol. 226, pp. 321-342) teaches the mannose receptor in the brain (see whole document).
Although the record may establish evidence of secondary considerations which are indicia of nonobviousness, the record may also establish such a strong case of obviousness that the objective evidence of nonobviousness is not sufficient to outweigh the evidence of obviousness. Newell Cos. v. Kenney Mfg. Co., 864 F.2d 757, 769, 9 USPQ2d 1417, 1427 (Fed. Cir. 1988), cert. denied, 493 U.S. 814 (1989); Richardson-Vicks, Inc., v. The Upjohn Co., 122 F.3d 1476, 1484, 44 USPQ2d 1181, 1187 (Fed. Cir. 1997). Applicant is reminded that the submission of objective evidence of patentability does not mandate a conclusion of patentability in and of itself. In re Chupp, 816 F.2d 643, 2 USPQ2d 1437 (Fed. Cir. 1987).
Conclusion
Claims 128, 129, 144 and 145 are pending and have been examined on the merits. Claims 128, 129, 144 and 145 remain 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.
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/IVAN A GREENE/ Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619
