DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The present application is drawn from PCT/IL2022/050753, filed 7/13/2022; and claims benefit under 35 U.S.C. 119(e) to U.S. Provisional application 63/221498, filed 7/14/2021.
Status of Claims
Claims 47-68 are pending and are being examined on the merits.
Claim Objections
Claim 55 is objected to because of the following informalities: Claim 55 recites a group consisting of anti-HER2+, anti-EGFR, anti-GD2, checkpoint inhibitor antibodies, and a fragment thereof. The “, and” makes it appear that a fragment is part of the group, rather than derivatives of the members of the group. It is suggested that claim 55 be amended to recite “a group consisting of anti-HER2+, anti-EGFR, anti-GD2 and checkpoint inhibitor antibodies, or the antigen-binding fragments thereof.” Appropriate correction is required.
Claim 60 is objected to because of the following informalities: Claim 60 recites “wherein the the first biologically active molecules is an antibody”. The phrase repeats the word “the” twice in succession. Further the word molecules is plural but followed by is, rather than are. It is suggested that molecule is singular, such that “the first biologically active molecule is an antibody.” Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 47-68 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 47 recites wherein the brain-internalizing transporter moiety is an insulin or an analog, a derivative, a conjugate or a fragment thereof. The specifications recite whereby the insulin molecules that may be used according to the present invention include but are not limited to: mammalian insulin, human insulin, recombinant insulin produced by any method known in the art, native and isolated insulin, fast-, rapid- and short-acting insulin and analogs, intermediate acting insulin and analogs, and long-acting insulin and analogs. Active fragments of any of the above-mentioned insulin molecules may be also used as long as they are capable of binding to endogenous receptors expressed at the human brain capillary endothelium cells and aiding the transport of molecules through the BBB,” (specs., pg. 14, lines 1-10). Thus, the specifications describe a variety of different insulin molecules based on function, but does not describe the structure of the “insulin analog, derivative, conjugate, or fragment thereof” that would allow one of skill in the art to readily determine whether a biological molecule meets the limitations of the claim. As such, one skilled in the art would be unable to readily delineate the metes and bounds of the claims. Therefore, claim 47 is rejected for indefiniteness regarding the required structure of the genus of insulin molecules for use in the multi-functional nanoparticle. Further, as claims 48-68 ultimately depend from claim 47, yet fail to rectify the indefiniteness of the insulin derivative, claims 48-68 are also rejected.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 47-68 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12569569 in view of Gao et al., (from IDS; J. Neuroimmune Pharmacol., 2016, 12) and Kumar et al., (Nature Protocols, 2008 3(2)), as evidenced by Chattopadhyay et al., (Molecular Pharmaceutics, 2010, 7(6)).
The instant claims are substantially similar to those of US ‘569, with the difference being the addition of a second biologically active agent conjugated to the, for example, insulin-coated gold nanoparticle, via a third linker.
US Patent ‘569 claims a nano-delivery system comprising an inorganic nanoparticle bound to a first and second linker wherein the first linker is 1000 Da larger in weight than the second linker, wherein the first linker is conjugated to a brain internalizing transporter moiety and the second linker is conjugated to a biologically active molecule or labeling molecule, and wherein the weight of the first and second linkers is 1000-10,000 Da (claim 1). US ‘569 also claims wherein the first and second linkers are non-cleavable (claim 2), wherein the nanoparticle is bound to the second linker via a sulfide bond and the biologically active agent is bound via an amide bond (claim 3); wherein the first and second linkers each constitute 5% mol to 60% mol of the total linkers bound to the nanoparticle (claim 4); wherein the biologically active agent may be an antibody or a small molecule (claim 5), wherein the linkers may be PEG, or SH-PEG-COOH or SH-PEG-NH2 (claims 6-7). US ‘569 also claims wherein the nano-delivery system further comprises a third linker which is monofunctional (claim 8), which may also be PEG (claim 9); and wherein the nanoparticle is metal, including gold or silver (claims 10-11), and wherein the brain-internalizing transporter moiety is insulin (claims 12-13), and wherein the nanoparticle has a diameter of 10-160 nm (claim 14). US ‘569 also claims pharmaceutical compositions, which may be formulated for IV administration (claims 15-16).
Thus, US ‘569 claims a nanoparticle conjugated with a biologically active agent and insulin, wherein the biologically active agent may be an antibody, and wherein the linker for the biologically active agent is shorter (i.e. at least 1 kDa lower MW) compared to the linker for insulin; US ‘569 also claims an optional third capped linker. The instant claims are drawn to an identical nanoparticle but further comprises a second biologically agent, which may also be an antibody, such that the nanoparticle has two first linkers, each conjugated to distinct antibodies, and a longer third linker conjugated to insulin.
Kumar et al. teaches the art that two different antibodies may be linked to gold nanoparticles using different PEG linkers (see Fig. 1). Kumar specifically uses gold nanoparticles and a heterofunctional linker attached to the Fc of the antibody, leaving the Fab portion unhindered (pg. 314, col. 2). The heterofunctional linker consists of an amide-bonded adipic hydrazide and a dithiol tether that is used to attach gold particles via covalent bonds. Kumar further teaches thiolated polyethylene glycol (PEG-SH) is used to coat any remaining bare gold surfaces to reduce nonspecific interactions (i.e. monofunctional capping). Kumar teaches “this conjugation strategy can easily be adapted to synthesize multifunctional contrast agents by attaching two or more different antibodies to each nanoparticle; this can be used for combining targeting and delivery on the same nanoparticle”, (pg. 314, col. 2). Kumar teaches attaching an anti-EGFR antibody to 20 nm gold particles (jpg. 314, col. 2), and that other types of linkers can be used to attach the antibody, such as an OPSS-PEF-NHS (pg. 315, col. 1, para. 2), whereby the NHS forms a covalent amide bond with the antibody. Specifically, Kumar demonstrates attaching a first anti-EGFR antibody and a second anti-biotin antibody to gold nanoparticles (see Fig. 1).
Regarding the optimization of the multifunctional particle, Gao teaches the art of dual targeting delivery systems for brain tumors (title), including wherein the particles are functionalized with two active targeting ligands” one to the blood-brain-barrier (BBB) and the other to the brain tumor (abstract). Gao teaches nanoparticle based drug delivery systems are an impressive non-invasive method to deliver drugs into brain tumors (pg. 6, col. 2, para. 2). Goa teaches PEG are used to link ligands onto nanoparticles (pg. 11, col. 2, para. 3; Linker Chemistry). Gao teaches a Cruz et al. study which conjugated antibodies to nanoparticles through PEG of various length to determine the influence of PEG length on cell targeting effect of the particles. Thus, Gao supports that PEGs of varying length may be used; further, the antibody conjugated nanoparticles of length 3000 showed a higher binding efficiency (pg. 12, col. 1, para. 1). Gao teaches the length of linkers for two ligands should be taken into consideration because one ligand may influence the other. Specifically, for the BBB targeting ligand, the linker should be longer to enable the ligand to effectively interact with the BBB, while the linker for the brain tumor targeting ligand should be shorter to minimize disturbing the interaction between the BBB targeting ligand and the BBB (pg. 12, col. 2 – col. 3). For example, while the authors prefer a PEG3400 length linker, Chen’s study used a PEG2000 length linker, and Li’s study used a PEG 1000 for conjugation of mannose, but a PEG 2000 for conjugation of (the BBB targeting) dequalinium (pg. 12, col. 1, para. 2). Thus, Gao teaches the art that multiple ligands can be attached to nanoparticles, including a ligand for targeting and crossing the BBB; that PEG linkers of various length may be used to link the ligands to the nanoparticles, but that the BBB targeting ligand should have a longer linker than the tumor targeting ligand, such as being at least 1000 Da greater as in Li’s study.
It would have been obvious to one of skill in the art to modify the dual ligand gold nanoparticles conjugated with a first linker to insulin and a second linker to an antibody, of US ‘569, to further comprise an additional biologically active agent, such as an antibody or chemotherapeutic drug, conjugated with a third linker. One would have been motivated to do so in order to improve the properties of the multifunctional particle for therapeutics, such as by adding probe molecules to nanoparticles for recognition and targeting, as taught by Kumar et al. There would have been a reasonable expectation for success given that two distinct antibodies may be attached to a gold nanoparticle, as taught by Kumar et al.; and that antibodies and BBB targeting moieties may be attached to the same nanoparticles, given that the length of the linker conjugating the BBB targeting moiety is longer (e.g. at least 1000 Da greater) than the length of the linker conjugating the antibodies or other biologically active agents, as taught by Gao et al. Thus, the invention was prima facie obvious to one of skill in the art at the time the invention was made.
Regarding claim 47; the combination of US ‘569, Kumar and Gao make obvious a gold nanoparticle with three linkers, whereby two linkers conjugate two distinct antibodies to the gold nanoparticle and a third linker conjugates insulin, and wherein the third linker is at least 1000 Da greater than the MW of the first and second linkers. Thus, US ‘569 claims 1, 5 and 12-13, in view of Kumar and Gao, make obvious instant claim 47.
Regarding claim 48, Kumar teaches attaching two distinct antibodies to a gold nanoparticle, and thus the combination of US ‘569, Kumar and Gao make obvious instant claim 48.
Regarding claims 49-51, 55 and 58-59. It is known in the art that a wide variety of PEG linkers are available for use, including PEG-SH linkers, with a thiol group ending, or PEG-COOH, or alternatively, SH-PEG-COOH heterobifunctional linkers. A skilled artisan would choose the appropriate PEG species based on the desired properties. Further, it is known that PEG linkers are polymeric, and the length of the PEG chain is variable. Gao teaches that PEG linkers for attaching moieties to nanoparticles have been investigated across varying lengths, as described above. This is further evidenced by Chattopadhyay et al. (Molecular Pharmaceutics, 2010). Chattopadhyay attaches the anti-HER2 antibody trastuzumab to gold nanoparticles using increasing ratios of PEG, from 0.6 to 18.9 PEG chains per trastuzumab, resulting in an increase in the MW of trastuzumab from approximately 150 kDa (see Fig. 2) to 240 kDa (abstract). Thus, it is clear that a skilled artisan may choose an appropriate PEG linker, which may be for example ~5 kDa MW for the longer linker, and choose a shorter PEG that is, for example, ~3.5 kDa MW (see Gao; PEG3500), based on the desired properties. Such selections are within the range of routine optimization based on commercially available linkers, under the guidance of US ‘569, Kumar and Gao, and as evidenced by Chattopadhyay. Thus, the combination of US ‘569 claims 6-7, Kumar and Gao, and as evidenced by Chattopadhyay, make obvious use of an antibody that is 130-200 kDa (claim 49), which may be an anti-EGFR antibody (Kumar et al.) or a HER2 antibody (claim 55), whereby the first and second linkers have a combined MW of at least 3,400 Da (claim 50), or whereby the insulin linker is 5000 Da and the antibody linkers are each 3500 Da (claim 51). Further, it is within the routine optimization of the skilled artisan to determine the relative concentration of each of the linked moieties on the nanoparticle, such that US ‘569 claim 4, Kumar and Gao make obvious instant claims 58-59.
Regarding claims 52-54. As described above, it is known in the art that various formats of PEG linkers are commercially available, including PEG linkers with a thiol group (SH) at one end, which forms a covalent sulfide bond with a gold nanoparticle (see Kumar); and/or a NHS group on the other end, which forms a covalent amide bond with an antibody. See also Chattopadhyay (Fig. 1), which attaches an H2N to the antibody, such that it will form an amide bond with an alternative OPSS-PEG-SVA linker through the SVA end. It is also known in the art that PEG linkers can be obtained which are cleavable or non-cleavable as desired. Thus, the combination of US ‘569 claims 2-3, Kumar and Gao, as evidenced by Chattopadhyay, make obvious instant claims 52-54.
Regarding claim 56; Kumar teaches gold nanoparticles of 20 nm diameter (pg. 314, col. 2). Thus, the combination of US ‘569 claims 10-11 and 14, and Kumar and Gao, as evidenced by Chattopadhyay make obvious instant claim 56.
Regarding claim 57; US ‘569 claims 8-9 claim mPEG monofunctional capping moiety, and Kumar teaches a monofunctional PEG-SH is “used to coat any remaining bare gold surfaces to reduce nonspecific interactions.” Thus, the combination of US ‘569 claims 8-9 and Kumar and Gao make obvious instant claim 57.
Regarding claims 60-63; US ‘569 claim 5 claims whereby the biologically active agent is a macromolecule, an antibody or a small molecule; wherein the small molecule may be the chemotherapeutic agent Cisplatin (col. 41, lines 51-54). Thus, as Kumar teaches conjugating two distinct antibodies and US ‘569 claims attaching a chemotherapeutic small molecule, the combination of US ‘569, Kumar and Gao make obvious a multifunctional nanoparticle with 2 or 3 biologically active agents conjugated to the insulin-coated nanoparticle, whereby the agents may be an antibody and a drug, or 2 antibodies and a drug. Thus, the combination of US ‘569, Kumar and Gao make obvious instant claims 60-61. Further, as the PEG linkers may be either cleavable or non-cleavable as desired under routine optimization, the combination of US ‘569, Kumar and Gao make obvious instant claims 62-63.
Regarding claim 64; US ‘569 claims a pharmaceutical composition comprising the nano-delivery system and a pharmaceutically acceptable carrier, wherein the composition is formulated for administration (claims 15-16). Thus, the combination of US ‘569, Kumar and Gao make obvious instant claim 64.
Regarding claims 65-68. The combination of US ‘569, Kumar and Gao makes obvious a multifunctional insulin-coated gold nanoparticle comprising an antibody and another biologically active agent, which may be a labeling molecule (US ‘569, claim 1), as described above. Gao teaches such particles for treatment of brain tumors (abstract) and administers an embodiment in glioma bearing nude mice and subsequently images the conjugated nanoparticles in vivo (pg. 9, Fig. 2).
It would have been obvious to one of skill in the art to administer the multifunctional nanoparticle of the combination of US ‘569, Kumar and Gao to a patient with a brain cancer. One would have been motivated to do so for therapeutic or for diagnostic imaging purposes, as taught by Gao et al. There would have been a reasonable expectation for success given that Gao administers multifunctional nanoparticles to mice with brain tumors and images the distribution of the nanoparticles in vivo for diagnostic purposes; and that the composition comprising the multifunctional nanoparticles are formulated for IV administration, as claimed by US ‘569. Thus, the method comprising administering the nanoparticle composition was prima facie obvious at the time the invention was made.
The combination of US ‘569, Kumar and Gao makes obvious multifunctional nanoparticles comprising insulin to pass through the BBB, and administration of such molecules in order to target brain tumors for treatment or imaging. Thus, the combination of US ‘569, Kumar and Gao make obvious a method of administering the multifunctional molecules of instant claims 65 and 68, as well as further comprising imaging the brain of the subject to evaluate accumulation of the multifunctional particle, of instant claim 67. Further, as the two biologically active agents or labeling agents are each conjugated to the gold nanoparticle with non-cleavable linkers, it is inherent that the two agents will exhibit synchronized distribution in the brain given that they are both attached to the gold nanoparticles and thus each nanoparticle will carry both agents to the same locations. Thus, the combination of US ‘569, Kumar and Gao make obvious instant claim 66.
Claims 47-68 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19/529,743 in view of Gao et al., (from IDS; J. Neuroimmune Pharmacol., 2016, 12) and Kumar et al., (Nature Protocols, 2008 3(2)).
Application ‘743 claims a method of treating a brain-related disease comprising administering a composition comprising a nano-delivery system, wherein the nano-delivery system is an inorganic molecule with a first and second linker, whereby the first linker is at least 1000 Da larger than the second linker (claim 1); whereby the method further comprises imaging the brain of the subject to evaluate accumulation of the nano-delivery system (claim 2), using a selected imaging system (claim 3), wherein the brain-related disorder is brain cancer (claims 4-5) or a neurodegenerative disorder (claim 6). The nano-delivery molecule of the methods of claim 1 comprises non-cleavable linkers (claim 7), wherein the bond to the inorganic nanoparticle is a sulfide bond and the bond to the active agent is an amide bond (claim 8), wherein the linkers each constitute 5% to 60% mol of the total linkers bound to the particle (claim 9), wherein the active agent is an antibody or a small molecule (claim 10), wherein the linkers are a PEG (claims 11-12), whereby the nanoparticle comprises a third linker which is monofunctional (claim 13), which may also be a PEG (claim 14), wherein the nanoparticle is gold (claims 15-16), wherein the brain-internalizing transporter is insulin (claims 17-18), wherein the diameter of the nanoparticle is 10-160 nm (claim 19) and whereby the composition is formulated for IV administration (claim 20).
The instant claims are substantially similar to those of the product used in the methods of application ‘743, with the difference being the addition of a second biologically active agent conjugated to the nanoparticle via a third linker.
Kumar et al. makes obvious conjugating two (or more) distinct antibodies on gold nanoparticles, using PEG linkers, as described above.
Gao makes obvious nanoparticles with various BBB penetrating agents combined with alternative biological agents linked, wherein the length of the linker to the BBB penetrating agent is at least 1000 Da longer than the linkers to the biologically active agents, as described above.
It would have been obvious to one of skill in the art to modify the nanoparticles comprising a BBB penetrating agent and a biologically active agent, of the methods of application ‘743, to further comprise a second biologically active agent. One would have been motivated to do so to improve the properties of the multifunctional particle for therapeutics, such as by adding probe molecules to nanoparticles for recognition and targeting, as taught by Kumar et al. There would have been a reasonable expectation for success given that two distinct antibodies may be attached to a gold nanoparticle, as taught by Kumar et al.; and that antibodies and BBB targeting moieties may be attached to the same nanoparticles, given that the length of the linker conjugating the BBB targeting moiety is longer (e.g. at least 1000 Da greater) than the length of the linker conjugating the antibodies or other biologically active agents, as taught by Gao et al. Thus, the invention was prima facie obvious to one of skill in the art at the time the invention was made.
Thus, the combination of application ‘743, Kumar and Gao make obvious, for example, a gold nanoparticle coated with insulin and further comprising a first antibody or small molecule and a second antibody or small molecule, wherein the size of the linker conjugating insulin is at least 1000 Da greater than the size of the linkers for the biologically active agents, and wherein the linkers are PEG derived such that a sulfide bond links to the nanoparticle and an amide bond links the agents.
The methods of application ‘743 claims 1-6, in view of Kumar and Gao, make obvious the compositions and methods of instant claims 64-68, as described above, whereby the synchronized distribution of two different agents within the brain is an inherent property of having two different agents linked to the same nanoparticles with non-cleavable linkers, thus synchronized distribution naturally flows from the design of the multifunctional molecule. The product of the methods of application ‘743 claims 1, 7-20, in view of Kumar and Gao, make obvious the product of instant claims 47-63. Specifically, Kumar teaches anti-EGFR antibodies linked to gold nanoparticles are known in the art, and it is within the routine optimization of the skilled artisan to choose an appropriate size of the antibody, the lengths and distribution proportions of the respective linkers and biologically active agents on the gold nanospheres, and whether to include a cleavable PEG linker with the third biologically active small molecule chemotherapeutic drug. Thus, the instant claims do not present a patentable novel distinction over the products and methods of the claims of application ‘743, in view of Kumar and Gao.
This is a provisional nonstatutory double patenting rejection.
Claims 47-48, 52-54 and 56-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-34 of copending Application No. 18/578403 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the scope of the claims of application ‘403 anticipate that of the instant claims. The instant claims are substantially similar to those of app ‘403, with the difference being that the instant claims require the BBB penetrating molecule attached to the inorganic particle to be insulin, whereas that of application ‘403 may be a genus of BBB targeting species, including insulin.
Specifically, app ‘403 claims a multifunctional particle comprising an inorganic particle bound to at least 3 linkers, with a biologically active molecule conjugated to two linkers and a brain internalizing transporter moiety conjugated to the third linker, wherein the length (size) of the third linker is at least 1000 Da greater than that of the first two linkers (claim 1), and whereby the brain-internalizing transporter may be insulin (claims 25-26). App ‘403 also claims whereby the linkers are PEG derivatives (claims 15-17), and whereby the biologically active agents may be antibodies or small molecules (claims 10-12). App ‘403 also claims a method of making the multifunctional particle (claims 30-34), which also encompasses the instantly claimed particle.
Specifically, app ‘403 claims 1-2, 5-9, 15-17, 21-26 and the methods of claims 30-34, anticipate instant claim 47; ‘403 claims 10-12 anticipate instant claim 48; ‘403 claims 3-4 anticipate instant claims 52 and 63, ‘403 claim 9 anticipates instant claims 53-54, ‘403 claims 27 anticipate instant claim 56, ‘403 claims 18-20 anticipate instant claim 57; ‘403 claims 13-14 anticipate instant claims 58-59; ‘403 claims 28-29 anticipates instant claims 60-62.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 47-68 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-34 of copending Application No. 18/578403 in view of Gao et al., (from IDS; J. Neuroimmune Pharmacol., 2016, 12) and Kumar et al., (Nature Protocols, 2008 3(2)).
The reasons why application ‘403 anticipates instant claims 47-48, 52-54 and 56-63 are described above. However, app ‘403 does not claim the respective size of the linkers (re. claims 50-51), the antibody (re. claims 49 and 55), or the compositions and methods (re. claims 64-68).
Regarding claims 50-51; the size of the respective linkers are made obvious via routine optimization following the guidance of Gao, as described above. Gao teaches that the length of the linker for the brain-internalizing moiety should be longer than that of the other linkers, including 1000 Da larger by example. Kumar teaches gold nanoparticles conjugated to two distinct antibodies via PEG linkers, and it is known that PEG linkers are commercially available with different sizes and lengths of the PEG repeating units. Thus, it is within the routine optimization of the skilled artisan to utilize PEG linkers whereby the weight of the first and second linkers is at least 3,400 Da and/or wherein each linker is 3500 Da, as described by Gao, and the third linker is 5000 Da. Thus, app ‘403, in view of Gao and Kumar, makes obvious instant claims 50-51.
Regarding claims 49 and 55; Kumar teaches that conjugating anti-EGFR antibodies to gold nanoparticles are known in the art, as described above. Further, it is within the routine optimization of the skilled artisan to choose such an antibody, or fragment thereof, that is 130-200 kDa. Thus, app ‘403, in view of Kumar, make obvious instant claims 49 and 55.
Regarding claims 64-68; the combination of app ‘403, Kumar and Gao makes obvious a multifunctional insulin-coated gold nanoparticle comprising an antibody and another biologically active agent, which may be a small molecule label (app. ‘403, claim 10), as described above. Gao teaches such particles for treatment of brain tumors (abstract) and administers an embodiment in glioma bearing nude mice and subsequently images the conjugated nanoparticles in vivo (pg. 9, Fig. 2).
It would have been obvious to one of skill in the art to administer the multifunctional nanoparticle of the combination of app ‘403, Kumar and Gao to a patient with a brain cancer. One would have been motivated to do so for therapeutic or for diagnostic imaging purposes, as taught by Gao et al. There would have been a reasonable expectation for success given that Gao administers multifunctional nanoparticles to mice with brain tumors and images the distribution of the nanoparticles in vivo for diagnostic purposes. Thus, the method comprising administering the nanoparticle composition was prima facie obvious at the time the invention was made.
The combination of app ‘403, Kumar and Gao makes obvious multifunctional nanoparticles comprising insulin to pass through the BBB, and administration of such molecules in order to target brain tumors for treatment or imaging. Thus, the combination of app ‘403, Kumar and Gao make obvious compositions comprising the multifunctional molecules of instant claim 64, a method of administering the multifunctional molecules of instant claims 65 and 68, as well as further comprising imaging the brain of the subject to evaluate accumulation of the multifunctional particle, of instant claim 67. Further, as the two biologically active agents or labeling agents are each conjugated to the gold nanoparticle with non-cleavable linkers, it is inherent that the two agents will exhibit synchronized distribution in the brain given that they are both attached to the gold nanoparticles and thus each nanoparticle will carry both agents to the same locations. Thus, the combination of app ‘403, Kumar and Gao make obvious instant claim 66.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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