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 .
Claim Status
Claims 1, 3-10, 13-15, 17-19, 25 and 34-42 are pending.
Claims 2, 11-12, 16, 20-24, and 26-33 were cancelled.
Claims 1, 25, 34, 36-37 are amended and claims 38-42 are new.
Claims 14-15 and 17-19 are withdrawn as being directed to a non-elected method invention, the election having been made on 12/24/2019.
Claims 1, 3-10, 13, 25, and 34-42 have been examined.
Priority
This application is a 371 of PCT/US2017/042307 07/17/2017.
PCT/US2017/042307 has PRO 62/363,395 07/18/2016.
Withdrawn Objection and Rejection
The objection to claims 5, 8-9, and 36 is withdrawn because the amendment to the claims overcome the objection.
The rejection of claims 1, 3-10, and 13 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn because the amendment to the claims overcome the rejection.
New Ground of rejection
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 41 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a NEW MATTER rejection.
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Applicant states “Claim 41 is supported, inter alia, by paragraph 00124 of the originally filed application” (Remarks, p22), but the paragraph 00124 of the originally filed application as shown follows does not support the molar concentration ratio range as claimed.
Maintained Rejection
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
1. Claims 1, 4-10, 13, 25, and 34-42 are rejected under 35 U.S.C. 103 as being unpatentable over Shelness (US 2003/0008014 Al, previously cited 1/31/2020) in view of Watkin (US 2006/0127467 A1, previously cited 1/31/2020), Ryan et al. (Expert Opin. Drug Deliv. (2008) 5(3):343-351, previously cited 1/14/2026) and Zhang et al. (US 2005/0175683, previously cited 1/14/2026).
Claim 1 is drawn to a nanolipoprotein particle comprising:
a membrane forming,
lipid, a lysolipid., and
a scaffold protein,
the membrane forming lipid and the lysolipid arranged in a discoidal membrane forming lipid bilayer stabilized by the scaffold protein,
the discoidal membrane forming lipid bilayer comprising the lysolipid in a molar concentration of about 10 to about 70 mol%.,
wherein the lysolipid is configured to function as a placeholder for the hydrophobic drug.
The wherein clause (vi) neither change the structure of a lysolipid nor a hydrophobic drug structure. Thus, prior art teachings meet the limitations (i)-(v) would satisfy the limitation (vi).
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With respect to limitations (i)-(iii), Shelness teaches a nanolipoprotein particle comprising: a membrane forming lipid and a recombinant scaffold protein arranged in a discoidal membrane of lipid bilayer, and recombinant discoidal complexes with a nanodisk structure are formed in the presence of apoB17F [0032] shown in figure 4 above, reading on the limitations of (i) and (iii). Shelness teaches the lipid composition further comprising at least one polar lipid, such as lysolipid, to form the nanolipoprotein complex [0054, claim 14], reading on the limitation (ii). Shelness shows the membrane forming lipid and the lysolipid arranged in a discoidal membrane forming lipid bilayer stabilized by the scaffold protein above (Fig 4).
Shelness does not specify a molar ratio of a lysolipid in the membrane of a nanolipoprotein particle.
With respect to limitations (ii), (iv) and (v), Watkin teaches the use of a lipid based nanoparticle (e.g., a nanolipoprotein particle of nanodisk) or a liposome as a drug carrier [Abstract, 0006, claim 2]. Watkin teaches a lipid bilayer or membrane of the lipid nanoparticle comprising a primary phospholipid (reading on membrane forming lipid) and a lysolipid [0006]. Watkin teaches the lysolipid may have a chain length ranging from about 6 to 24 carbon atoms, with a preferred chain length of about 14 carbon atoms [0027], such as l-tetradecanoyl-snglycero-3-phosphocholine
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(lyso14:0; the elected lysolipid species) as shown follows[Fig 3b]. Watkin suggests the molar ratio of phospholipid to the lysolipid is a result effective variable ranged from about 80:20 to about 95:5 and preferably about 90: 10 [0030], reading on the limitations (ii), (iv), and (v).
With respect to limitation (vi) of wherein clause, Ryan et al. is cited to show nanodisks (NDs) as hydrophobic drug delivery vehicles known in the art (Title). Ryan et al. show the common knowledge of nanodisks as hydrophobic drug delivery vehicles comprising (a) the edge of the ND is stabilized through apolipoprotein, a scaffold protein, binding to the disk perimeter (p344, Fig 1, legend), (b) NDs do not possess an aqueous core (c) scaffold proteins constitute an intrinsic structural element of NDs, (d) ND diameters much smaller than liposome, and (e) unlike liposomes, NDs are fully soluble in aqueous media (p344, col 1, 1.1 Nanodisk structure). Thus, one of ordinary skill in the art would have known different properties between Shelness’s ND and liposome are (a)-(e) listed above even though they may contain the same phospholipids and lysolipids. Zhang et al. is further cited to show common knowledge that lysolipids, e.g., lysophosphatidylcholine, having one hydrocarbon chain serves as surfactant (not a lipid bilayer forming lipid) interacting with a hydrophobic compound in a lipid bilayer vesicle [0035-0036], reading on the wherein clause “lysophosphatidylcholine with surfactant function as a placeholder in Shelness’s discoidal membrane forming lipid bilayer for incorporation of molecules of a hydrophobic drug of paclitaxel in the discoidal membrane forming lipid bilayer” as shown in Shelness’s figure 4 above. Furthermore, Shelness in view of Watkin teaches a nanolipoprotein particle (nanodisk known in the art) comprising a membrane forming lipid, a lysolipid, and a recombinant scaffold protein. Lysolipids, e.g., lysophosphatidylcholine, having one hydrocarbon chain serves as surfactant in a lipid bilayer vesicle known in the art evidenced by Zhang et al. [0035-0036]. One of ordinary skill in the art would have known to optimize the amount of lysolipid in the nanolipoprotein particle (nanodisk) below critical micelle concentration of the lysolipid (CMC) to avoid micelle formation according to Watkin’s suggestion for the molar ratio of phospholipid to the lysolipid is a result effective variable ranged from 80:20 to about 95:5 and preferably about 90:10 [0030], reading on the limitations (i)-(v) described above. The specification [00129] disclosed “once the drugs are incorporated and the lysolipids will be expulsed from the assembled NLPs”, that is to say, if lysolipids are not excluded then a hydrophobic drug CANNOT be incorporated into the nanolipoprotein particle. Since Shelness’s hydrophobic drug of paclitaxel incorporated into the nanolipoprotein particle (Fig 4) is the same drug used by applicant [00165-00166], the limitation (vi) is necessary to be satisfied in the nanolipoprotein particle (nanodisk) taught by Shelness in view of Watkin, reading on claims 1 and 6.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine Shelness's nanolipoprotein bilayer particle with Watkin's lysolipid of 1-tetradecanoyl-snglycero phosphocholine (lyso14:0) because (i) Shelness teach a lipid bilayer nanolipoprotein particle comprising a lysolipid as a drug carrier [0054] and (ii) Watkin teaches the use of lysolipid 14:0 of l-tetradecanoyl-snglycero-3-phosphocholine (Fig 3b) compatible with phospholipid to make a lipid bilayer of a drug delivery vehicle. The combination would have reasonable expectation of success because both references teach lysolipid in a lipid bilayer of drug delivery vehicle.
Ryan et al. is cited as evidence to show the common knowledge of nanodisks as hydrophobic drug delivery vehicles (p344, col 1, 1.1 Nanodisk structure). Zhang et al. is further cited as evidence to show common knowledge that lysolipids having one hydrocarbon chain serves as surfactant in a lipid bilayer vesicle [0035-0036] able to interact with a hydrophobic drug via hydrophobic interaction force, serving as a placeholder in Shelness’s discoidal membrane forming lipid bilayer for incorporation of molecules of a hydrophobic drug of paclitaxel in the discoidal membrane forming lipid bilayer.
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With respect to claims 4-5, Shelness teach the truncated scaffold protein can be optimized from 0.5% to 90% [0073]. Shelness further teaches apoB is capable of stabilizing the bilayer particle for controlling the size of the nanolipoprotein particle [0065, Fig 4]. Thus, the molar ratio of a scaffold protein in a nanolipoprotein bilayer particle is a result effective variable, which can be optimized through routine experimentation. MPEP 2144.05 (II) states “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
With respect to claims 7-10, Watkin show the lysolipid (Fig 3b) is l-tetradecanoyl-snglycero-3-phosphocholine (lyso14:0; the elected lysolipid species), reading on the elected species in claims 7-10.
With respect to claim 13, Shelness teaches truncated apoB as a fusion protein with a single chain antibody, ligand or receptor, or any other peptide sequence that would be specific for a particular macromolecular cell surface marker [0024]. Shelness teaches the use of truncated apoB to compartmentalize lipophilic drugs, such as paclitaxel in a nanolipoprotein particle [0018, Fig 2-4], reading on a functionalized amphipathic compound.
With respect to claim 25, Shelness in view of Watkin teach a hydrophobic drug delivery system comprising nanolipoprotein particles and a process of making the nanolipoprotein particle. Shelness teaches a nanolipoprotein particle comprising a membrane forming lipid of phospholipids and lysolipids [0054] as well as a scaffold protein [0058]. Shelness shows upon assembly the one or more membrane forming lipids and the scaffold protein provide a discoidal membrane lipid bilayer for the nanolipoprotein particle in which the one or more lysolipids are comprised within the discoidal membrane lipid bilayer in the system (Fig 4). Shelness shows the scaffold protein able to stabilize phospholipids and lysolipids in the system in figure 4 (known as nanodisk/ND) and further evidenced by Ryan’s teaching that the edge of ND is stabilized through apolipoprotein binding to the disk perimeter (p344, Fig 1, legend). Watkin suggests the molar ratio of membrane-forming phospholipid to the lysolipid is a result effective variable ranged from 80:20 to about 95:5 and preferably about 90: 10, equal to 9:1, [0030] in the system. Watkin teaches the lysolipid in the system may have a chain length ranging from about 6 to 24 carbon atoms, with a preferred chain length of about 14 carbon atoms [0027], such as l-tetradecanoyl-snglycero-3-phosphocholine (lyso14:0; the elected lysolipid species), shown in figure 3b. Also See rejection of claim 1 above.
With respect to claim 34, see rejection of claim 1 above. Claim 34 has broader claim scope than the rejected claim 1 above.
With respect to claim 35, Watkin teaches the lysolipid may have a chain length ranging from about 6 to 24 carbon atoms, with a preferred chain length of about 14 carbon atoms [0027], such as l-tetradecanoyl-snglycero-3-phosphocholine (lyso14:0; the elected lysolipid species), comprising a chain length of 14 carbons [Fig 3b].
With respect to claim 36, Zhang et al. is cited to show common knowledge that lysolipids, e.g., lysophosphatidylcholine, having one hydrocarbon chain serves as surfactant in a lipid bilayer vesicle [0035-0036]. One of ordinary skill in the art would have known to optimize the amount of lysolipid in the nanolipoprotein particle (nanodisk) below critical micelle concentration of the lysolipid (CMC) to avoid micelle formation. Furthermore, Watkin’s lysolipid of l-tetradecanoyl-snglycero-3-phosphocholine (lyso14:0; the elected lysolipid species) has the CMC value of 80 µM disclosed in the specification [00180].
With respect to claim 37, Watkin show the lysolipid (Fig 3b) is l-tetradecanoyl-snglycero-3-phosphocholine (lyso14:0; the elected lysolipid species) including a saturated hydrocarbon.
With respect to claim 38, Ryan et al. show the common knowledge of nanodisks as hydrophobic drug delivery vehicles comprising (a) the edge of the ND is stabilized through apolipoprotein, a scaffold protein, binding to the disk perimeter (p344, Fig 1, legend), (b) NDs do not possess an aqueous core (c) scaffold proteins constitute an intrinsic structural element of NDs, (d) ND diameters much smaller than liposome, and (e) unlike liposomes, NDs are fully soluble in aqueous media (p344, col 1, 1.1 Nanodisk structure). Zhang et al. is further cited to show common knowledge that lysolipids, e.g., lysophosphatidylcholine, having one hydrocarbon chain serves as surfactant (not a lipid bilayer forming lipid) in a lipid bilayer vesicle [0035-0036]. Thus, it is expected that the lysolipid as a surfactant is expulsed from the nanolipoprotein particle after incorporation of the hydrophobic drug. Furthermore, applicant disclosed once the hydrophobic drugs are incorporated and the lysolipids will be expulsed from the assembled NLPs as shown follows [00129].
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With respect to claim 39-40, applicant show the hydrophobic drug is paclitaxel (Fig 4).
With respect to claim 41, a molar concentration ratio of membrane forming lipids: lysolipids: scaffold protein for delivery of a hydrophobic drug is a result effective variable, which can be optimized based on the amount of a hydrophobic drug used under prior art conditions. see 2144.05 (II).
With respect to claim 42, Zhang et al. teach common knowledge that lysolipids, e.g., lysophosphatidylcholine, having one hydrocarbon chain serves as surfactant (not a lipid bilayer forming lipid) in a lipid bilayer vesicle [0035-0036] able to interact with a hydrophobic drug via hydrophobic interaction force, serving as a placeholder in Shelness’s discoidal membrane forming lipid bilayer for incorporation of molecules of a hydrophobic drug of paclitaxel in the discoidal membrane forming lipid bilayer. Since the binding of lysophosphatidylcholine to a hydrophobic drug has a limitation in Shelness’s nanolipoprotein particle, one of ordinary skill in the art would have found it obvious to optimize the molar ratio of a hydrophobic drug to a lysolipid, such as l-tetradecanoyl-snglycero-3-phosphocholine (lyso14:0) shown in Watkin’s Fig 3b.
Applicant’s Arguments
Shelness does not disclose lysolipids stabilized in the discoidal membrane forming lipid bilayer as being a placeholder for a hydrophobic drug, as required in amended claim 1 (Remarks, p18, para 2).
Shelness disclosed apoB and lysolipid-type polar lipids in a mono-lipid layer in Figs 2B; thus, Shelness did not disclose apoB and lysolipid-type polar lipids in a lipid bi-layer (Remarks, p18, para 3).
The amendment to claim 25 overcomes the rejection of record (Remarks, p19, last two para to p20, para 1-2).
The amendment to claim 34 overcomes the rejection of record because (i) Shelness does not disclose paclitaxel positioned in Shelness's lipoprotein particles in some sites formerly occupied by lysolipid, as required in amended claim 34 and (ii) Shelness disclosed apoB and lysolipid-type polar lipids in a mono-lipid layer in Figs 2B; thus, Shelness did not disclose apoB and lysolipid-type polar lipids in a lipid bi-layer (Remarks, p20, Sec, claim 34 to p21, whole page).
Response to Arguments
Applicant's arguments filed 4/14/2026 have been fully considered but they are not persuasive for the reasons as follows.
Applicant’s argument (i) is not persuasive because (a) Ryan et al. teach NDs do not possess an aqueous core (p344, col 1, 1.1 Nanodisk structure) and (b) Zhang et al. is further cited to show common knowledge that lysolipids, e.g., lysophosphatidylcholine, having one hydrocarbon chain serves as surfactant (not a lipid bilayer forming lipid) in a lipid bilayer vesicle [0035-0036]. As a physical law of nature, the hydrocarbon chain of lysophosphatidylcholine is expected to interact with the hydrophobic drug of paclitaxel via hydrophobic interaction force reading on lysolipids serving as a placeholder for the hydrophobic drug within the discoidal membrane forming lipid bilayer as taught by the cited references. The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in
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the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992. See MPEP 2144(I).
Applicant’s argument (ii) is not persuasive because applicant narrowly interprets Shelness’s teachings. Shelness et al. explicitly show the other embodiment of apoB and lysolipid-type polar lipids in a lipid bilayer in Figs 2B evidenced as follows. Also see Decision on Appeal dated 9/25/2025.
Applicant’s argument (iii) is not persuasive because the amendment to claim 25 fails to satisfy the rejection of record. See the rejection at page 11 above. A molar ratio of phospholipid to lysolipid in a hydrophobic drug delivery system is a result effective variable, which can be optimized through routine experimentation evidenced by Leigh et al. (US 6599527 B1, previously cited 1/31/2020) used for the following rejection. Also see 2144.05 (II).
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Applicant’s argument (iv) is not persuasive because (a) Ryan et al. teach NDs do not possess an aqueous core (p344, col 1, 1.1 Nanodisk structure) and (b) Zhang et al. is further cited to show common knowledge that lysolipids, e.g., lysophosphatidylcholine, having one hydrocarbon chain serves as surfactant (not a lipid bilayer forming lipid) in a lipid bilayer vesicle [0035-0036]. As a physical law of nature, the hydrocarbon chain of lysophosphatidylcholine is expected to interact with the hydrophobic drug of paclitaxel via hydrophobic interaction force (non-covalent force), serving as a placeholder for the hydrophobic drug within the discoidal membrane forming lipid bilayer as taught by the cited references. The specification [00129] disclosed “once the drugs are incorporated and the lysolipids will be expulsed from the assembled NLPs”, that is to say, if lysolipids are not excluded then a hydrophobic drug CANNOT be incorporated into the nanolipoprotein particle. Furthermore, Shelness et al. explicitly show the other embodiment of apoB and lysolipid-type polar lipids in a lipid bilayer in Figs 2B evidenced as follows. Also see Decision on Appeal dated 9/25/2025.
2. Claims 1, 3-10, 13, 25, and 34-42 are rejected under 35 U.S.C. 103 as being unpatentable over Shelness (US 2003/0008014 Al, previously cited 1/31/2020) in view of Leigh et al. (US 6599527 B1, previously cited 1/31/2020) and evidenced by (a) Ryan et al. (Expert Opin. Drug Deliv. (2008) 5(3):343-351, previously cited 1/14/2026), (b) Zhang et al. (US 2005/0175683, previously cited 1/14/2026), and (c) Zock et al. (Arterioscler Thromb. 1994 Apr;14(4):567-75, previously cited 1/14/2026).
Claim 1 is drawn to a nanolipoprotein particle comprising:
a membrane forming,
lipid, a lysolipid., and
a scaffold protein,
the membrane forming lipid and the lysolipid arranged in a discoidal membrane forming lipid bilayer stabilized by the scaffold protein,
the discoidal membrane forming lipid bilayer comprising the lysolipid in a molar
concentration of about 10 to about 70 mol%.,
wherein the lysolipid is configured to function as a placeholder for the hydrophobic drug.
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With respect to limitations (i)-(iii), Shelness teaches a nanolipoprotein particle comprising: a membrane forming lipid and a recombinant scaffold protein arranged in a discoidal membrane of lipid bilayer, and recombinant discoidal complexes with a nanodisk structure are formed in the presence of apoB17F [0032] shown in figure 4 above, reading on the limitations of (i) and (iii). Shelness teaches the lipid composition further comprising at least one polar lipid, such as lysolipid, to form the nanolipoprotein complex [0054, claim 14], reading on the limitation (ii). Shelness shows the membrane forming lipid and the lysolipid arranged in a discoidal membrane forming lipid bilayer stabilized by the scaffold protein above (Fig 4).
Shelness does not specify a molar ratio of a lysolipid in the membrane of a nanolipoprotein particle.
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Similarly, Leigh et al. teach the use of a lipid bilayer comprising a mixture of membrane forming lipid and lysolipid for drug delivery (Fig 1B). Leigh et al. show that phosphatidylcholine (PC) to a lysophospholipid of mono-acyl phosphatidyl choline (MAPC) at an optimized ratio of 60:40 can beneficially increase the amount of a delivered lipophilic drug carried by the nanolipoprotein particle (Fig 10), reading on the limitation of lysolipid in a molar concentration of about 10 to about 70 mol%. Leigh et al. suggest the phosphatidyl choline (PC) and monoacyl phosphatidyl choline (MAPC) are endogenous compounds (col 6, line 2-3). The common endogenous fatty acids are palmitate (linear C16) or myristic acid (linear C14) well-known in the art. Leigh's mono-acyl phosphatidyl choline (MAPC) reads on the compound formulas (I) and (Ia) shown as follows; wherein R1 is C13 or C15 alkyl. When R1=C13, Q1=Q2=O, n=1, 0=0, m=2, R21=H, and Z= choline, the compound formula reads on a lysolipid of l-tetradecanoyl-snglycero-3-phosphocholine (lyso14:0 with CPC of 80 µM as disclosed in the specification [00180]), reading on the limitation of a lysolipid with CMC value ranging between 0.0005 to 100 mM. Because both Shelness and Leigh et al. teach a lipid bilayer drug delivery vehicle comprising phospholipid and lysolipid, one of ordinary skill in the art would have found it obvious to use phosphatidylcholine (PC) to a lysophospholipid of mono-acyl phosphatidyl choline (MAPC) at ratio of 60:40 to increase the amount of a delivered lipophilic drug carried by the nanolipoprotein particle (Fig 10), reading on the limitations of (ii), (iv), and (v).
With respect to limitations (ii), (iv), and (v), Ryan et al. is cited to show nanodisks (NDs) as hydrophobic drug delivery vehicles known in the art (Title). Ryan et al. show the common knowledge of nanodisks as hydrophobic drug delivery vehicles comprising (a) the edge of the ND is stabilized through apolipoprotein binding to the disk perimeter (p344, Fig 1, legend), (b) NDs do not possess an aqueous core (c) scaffold proteins constitute an intrinsic structural element of NDs, (d) ND diameters much smaller than liposome, and (e) unlike liposomes, NDs are fully soluble in aqueous media (p344, col 1, 1.1 Nanodisk structure). Thus, one of ordinary skill in the art would have known major different properties between Shelness’s ND and liposome are (a)-(e) listed above even though they may contain the same phospholipids and lysolipids. Zhang et al. is cited to show common knowledge that lysolipids, e.g., lysophosphatidylcholine, having one hydrocarbon chain serves as surfactant in a lipid bilayer vesicle [0035-0036].
With respect to limitation (vi), Shelness in view of Leigh teaches a nanolipoprotein particle (nanodisk known in the art) comprising a membrane forming lipid, a lysolipid, and a recombinant scaffold protein. Lysolipids, e.g., lysophosphatidylcholine, having one hydrocarbon chain serves as surfactant in a lipid bilayer vesicle known in the art evidenced by Zhang et al. [0035-0036]. One of ordinary skill in the art would have known to optimize the amount of lysolipid in the nanolipoprotein particle (nanodisk) below critical micelle concentration of the lysolipid (CMC) to avoid micelle formation as applied to the limitations (i)-(v) above. The specification [00129] disclosed “once the drugs are incorporated and the lysolipids will be expulsed from the assembled NLPs.” Since Shelness’s hydrophobic drug of paclitaxel (Fig 4) is the same drug used by applicant [00165-00166], the limitation (vi) is necessary to be in the nanolipoprotein particle (nanodisk) as taught by Shelness in view of Leigh.
Thus, Shelness in view of Leigh et al. and evidenced by (a) Ryan et al. and (b) Zhang et al. are obvious to the instant claims 1, 3, and 6.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine Shelness's nanolipoprotein bilayer particle with Leigh's lysolipid of 1-tetradecanoyl-snglycero phosphocholine (lyso14:0) because (i) Shelness teach a lipid bilayer nanolipoprotein particle comprising a phospholipid (e.g., phosphatidylcholine) and a lysolipid as a drug delivery vehicle of a nanolipoprotein [0054] and (ii) Leigh et al. show that phosphatidylcholine (PC) to a lysophospholipid of mono-acyl phosphatidyl choline (MAPC) at an optimized ratio of 60:40 can beneficially increase the amount of a delivered lipophilic drug carried by the nanolipoprotein particle (Fig 10). The combination would have reasonable expectation of success because both references teach the use of a nanolipoprotein comprising phosphatidylcholine and lysophospholipid to deliver a hydrophobic or lipophilic drug.
Ryan et al. is cited as evidence to show the common knowledge of nanodisks as hydrophobic drug delivery vehicles (p344, col 1, 1.1 Nanodisk structure). Zhang et al. is further cited as evidence to show common knowledge that lysolipids having one hydrocarbon chain serves as surfactant in a lipid bilayer vesicle [0035-0036]. Zoac et al. is further cited as evidenced to show endogenous fatty acids of palmitate (linear C16) or myristic acid (linear C14) well-known in the art by (p567, col 1).
With respect to claims 4-5, Shelness teach the truncated scaffold protein can be optimized from 0.5% to 90% [0073]. Shelness further teaches apoB is capable of stabilizing the bilayer particle for controlling the size of the nanolipoprotein particle [0065, Fig 4]. Thus, the molar ratio of a scaffold protein in a nanolipoprotein bilayer particle is a result effective variable, which can be optimized through routine experimentation. MPEP 2144.05 (II) states “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
With respect to claim 7, Leigh et al. teach the lysolipid of MAPC is mono-acyl phosphatidyl choline (col 5, line 36-38), reading on lysophospholipids.
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With respect to claims 8-10, Leigh et al. suggest the phosphatidyl choline (PC) and monoacyl phosphatidyl choline (MAPC) are endogenous compounds (col 6, line 2-3). The common endogenous fatty acids are palmitate (linear C16) or myristic acid (linear C14) well-known in the art as evidenced by Zoac et al. (p567, col 1). Leigh's mono-acyl phosphatidyl choline (MAPC) reads on the compound formulas (I) and (Ia) shown above; wherein R1 is C13 or C15 alkyl. A lysolipid of myristic acid (R1=C13) reads on the elected species of l-tetradecanoyl-sn-glycero-3-phosphocholine (lyso 14:0).
With respect to claim 13, Shelness teaches truncated apoB as a fusion protein with a single chain antibody, ligand or receptor, or any other peptide sequence that would be specific for a particular macromolecular cell surface marker [0024]. Shelness teaches the use of truncated apoB to compartmentalize lipophilic drugs, such as paclitaxel in a nanolipoprotein particle [0018, Fig 2-4], reading on a functionalized amphipathic compound.
With respect to claim 25, Shelness in view of Leigh et al. teach a nanolipoprotein particle comprising a membrane forming lipid of phospholipids and lysolipids as well as a scaffold protein in a composition/system. Shelness teaches the system/composition comprising a membrane forming lipid of phospholipids and lysolipids [0054] as well as a scaffold protein [0058]. Shelness shows upon assembly the one or more membrane forming lipids and the scaffold protein provide a discoidal membrane lipid bilayer for the nanolipoprotein particle in which the one or more lysolipids are comprised within the discoidal membrane lipid bilayer in the system (Fig 4). Shelness shows the scaffold protein able to stabilize phospholipids and lysolipids in the system in figure 4 (known as nanodisk/ND) and further evidenced by Ryan’s teaching that the edge of ND is stabilized through apolipoprotein binding to the disk perimeter (p344, Fig 1, legend). Leigh et al. suggest that molar ratio of phosphatidylcholine (PC) to a lysophospholipid of mono-acyl phosphatidyl choline (MAPC) as an result effective variable and an optimized ratio of 60:40 can beneficially increase the amount of a delivered lipophilic drug carried by the nanolipoprotein particle (Fig 10) in the system. Leigh et al. further suggest a lysolipid of mono-acyl phosphatidyl choline (MAPC) in the system as reading on the compound formulas (I) and (Ia); wherein R1 is C13 or C15 alkyl. When R1=C13, Q1=Q2=O, n=1, 0=0, m=2, R21=H, and Z= choline. Leigh’s Lysolipid reads on the compound of l-tetradecanoyl-snglycero-3-phosphocholine (lyso14:0 with CPC of 80 µM as disclosed in the specification [00180]). Also See rejection of claim 1 above.
With respect to claim 34, see rejection of claim 1 above. Claim 34 has broader claim scope than the rejected claim 1 above.
With respect to claim 35, Leigh's mono-acyl phosphatidyl choline (MAPC) reads on the compound formulas (I) and (Ia) shown above; wherein R1 is C13 or C15 alkyl. A lysolipid of myristic acid (R1=C13) reads on the elected species of l-tetradecanoyl-sn-glycero-3-phosphocholine (lyso 14:0). See rejection of claims 8-10 above.
With respect to claim 36, Zhang et al. is cited to show common knowledge that lysolipids, e.g., lysophosphatidylcholine, having one hydrocarbon chain serves as surfactant in a lipid bilayer vesicle [0035-0036]. One of ordinary skill in the art would have known to optimize the amount of lysolipid in the nanolipoprotein particle (nanodisk) below critical micelle concentration of the lysolipid (CMC) to avoid micelle formation. Furthermore, Leigh’s Lysolipid reads on the elected
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compound of l-tetradecanoyl-snglycero-3-phosphocholine (lyso14:0) with CPC of 80 µM as disclosed in the specification [00180].
With respect to claim 37, Leigh’s lysolipid as shown follows includes a saturated hydrocarbon.
With respect to claim 38, Ryan et al. show the common knowledge of nanodisks as hydrophobic drug delivery vehicles comprising (a) the edge of the ND is stabilized through apolipoprotein, a scaffold protein, binding to the disk perimeter (p344, Fig 1, legend), (b) NDs do not possess an aqueous core (c) scaffold proteins constitute an intrinsic structural element of NDs, (d) ND diameters much smaller than liposome, and (e) unlike liposomes, NDs are fully soluble in aqueous media (p344, col 1, 1.1 Nanodisk structure). Zhang et al. is further cited to show common knowledge that lysolipids, e.g., lysophosphatidylcholine, having one hydrocarbon chain serves as surfactant (not a lipid bilayer forming lipid) in a lipid bilayer vesicle [0035-0036]. Thus, it is expected that the lysolipid as a surfactant is expulsed from the nanolipoprotein particle after incorporation of the hydrophobic drug. Furthermore, applicant disclosed once the hydrophobic drugs are incorporated and the lysolipids will be expulsed from the assembled NLPs as shown follows [00129].
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With respect to claim 39-40, Shelness et al. show the hydrophobic drug is paclitaxel (Fig 4).
With respect to claim 41, a molar concentration ratio of membrane forming lipids: lysolipids: scaffold protein for delivery of a hydrophobic drug is a result effective variable, which can be optimized based on the amount of a hydrophobic drug used under prior art conditions. see 2144.05 (II).
With respect to claim 42, Zhang et al. teach common knowledge that lysolipids, e.g., lysophosphatidylcholine, having one hydrocarbon chain serves as surfactant (not a lipid bilayer forming lipid) in a lipid bilayer vesicle [0035-0036] able to interact with a hydrophobic drug via hydrophobic interaction force, serving as a placeholder in Shelness’s discoidal membrane forming lipid bilayer for incorporation of molecules of a hydrophobic drug of paclitaxel in the discoidal membrane forming lipid bilayer. Since the binding of lysophosphatidylcholine to a hydrophobic drug has a limitation in Shelness’s nanolipoprotein particle, one of ordinary skill in the art would have found it obvious to optimize the molar ratio of a hydrophobic drug to a lysolipid taught by Leigh.
Applicant’s Argument
Leigh, Ryan, Zhang, and Zoac are applied as secondary references to disclose lysolipids interspersed in a lipid bilayer may form a nanoprotein particle, nanodisks may be used as drug delivery vehicles, lysolipids may be present as surfactants in a lipid bilayer, and the claimed lysolipid is a common lysolipid, respectively, NFOA at 14-18. However, none of the secondary references disclose evidence that Shelness's apolipoprotein forms a discoidal lipoprotein particle having lysolipids stabilized by the apolipoprotein. Applicant respectfully requests reconsideration and allowance of claim 1 (Remarks, p18 last para).
Response to Arguments
Applicant's arguments filed 4/14/2026 have been fully considered but they are not persuasive because Zhang et al. is cited to show common knowledge that lysolipids, e.g., lysophosphatidylcholine, having one hydrocarbon chain serves as surfactant (not a lipid bilayer forming lipid) in a lipid bilayer vesicle [0035-0036]. As a physical law of nature, the hydrocarbon chain of lysophosphatidylcholine is expected to interact with the hydrophobic drug of paclitaxel via hydrophobic interaction force and serve as a placeholder for stabilizing the hydrophobic drug within the discoidal membrane forming lipid bilayer as taught by the cited references described above.
Conclusion
No claim is allowed.
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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/J.L/Examiner, Art Unit 1658
29-June-2026
/Melissa L Fisher/ Supervisory Patent Examiner, Art Unit 1658
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