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 .
Election/Restrictions
Applicant’s election without traverse of Group I (i.e., Claims 1-20, drawn to an aqueous compositing comprising a population of HDL mimetic micellular nanoparticles) in the reply filed on 11/06/2025 is acknowledged. Additionally, Applicant’s representative (i.e., Michael Curts) confirm the election without traverse of Species A (i.e., a single and specific amphiphilic, alpha-helical peptide indicating: single and specific SEQ ID NO, Applicant’s Election: SEQ ID NO: 35; and a single and specific paclitaxel-anchor moiety from Table 6, Applicant’s Election: moiety No. 78, i.e., Paclitaxel-γ-tocotrienol conjugate with a cleavable carbonate bond) during a telephonic call on 11/21/2025.
Claims 21-29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, likewise claims 16-18 and 20 are withdrawn from further consideration as being drawn to a nonelected species; there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/06/2025.
Upon searching the elected species (i.e., moiety No. 78, i.e., Paclitaxel-γ-tocotrienol conjugate with a cleavable carbonate bond)), additional species were found, e.g., moiety No. 71 (i.e., paclitaxel-cholesterol conjugate with a cleavable carbonate bond) and moiety No. 79 (i.e., paclitaxel-δ-tocotrienol with a cleavable carbonate bond). Accordingly, for purposes of compact prosecution, the election of species is modified only to the extent of examining these additional species. Otherwise the election of species requirement is still retained.
Claim Status
Claims 1-30 were originally filed on 05/09/2025.
Sequence Interpretation
For claims 2, 9 and 20, please note that the Examiner is interpreting the scope of the amphiphilic alpha-helical peptide as comprising 100% identity to SEQ ID NO: 35 (i.e., Applicant’s Elected species).
Priority
The present application claims the benefit under 35 U.S.C 119 (e) to U.S. Provisional Application No. 63/645,127 filed 05/09/2024. 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, or 365 (c ) is acknowledged.
Specification
The disclosure is objected to because of the following informalities: missing figures. Example 19 on pg. 87, para[0302] refers to Figures 21-A through 21-L depicting a set of conjugates. However, the drawings filed on 05/09/2025 only illustrate up to Figure 18N. It is also noted that the specification is silent about Figures 19 and 20. Appropriate correction is required.
Claim Objections
Claims 1-29 are objected to because of the following informalities: Acronym. Claim 1 recites, “C-m-HDLs” Although, the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The Examiner respectfully requests that Applicant uses “chemotherapeutic micellular HDL” for the first recitation, thereafter “C-m-HDLs” may be utilized. Appropriate correction is required.
Claims 15 is objected to because of the following informalities: Duplicate claim numbering. All of the claims presented in a claim listing shall be presented in ascending numerical order. Since there are two claims numbered as “Claim 15”; however the claims recite different content and are not duplicate of each other. The Examiner is reading the duplicate claim 15 as claim 16, and all the subsequent claims in numerical ascending order. Appropriate correction is required.
Claim 19 (i.e., renumber claim 20), is objected to because of the following informalities: Grammar, use of the wrong transitive verb (i.e., provided). Applicants can amend the claim by using the transitive verb represented (i.e., “amino acid sequence represented by SEQ ID NO: 35”). Appropriate correction is required.
It is noted that that the claims are grouped by inventions and are in separate pages. For instance, claims 1-8 drawn to an aqueous composition are listed at pp. 1-2; claims 9-20 drawn to a population of C-m-HDLs are listed at pp. 3-4; and claims 21-30 drawn to a method for treating are listed at pp. 5-6. This method of grouping the claims creates confusion when examining. No gaps or blank spaces constituting more than two line spaces should separate the claims presented in ascending numerical order. 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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
1. Claims 1-15, duplicate 15 (i.e., renumbered claim 16) and duplicate claim 19 (i.e., renumbered claim 20) 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. Independent claim 1, recites that the population of C-m-HDLs comprises: “i) an amphiphilic, alpha-helical peptide or protein wherein said peptide or protein is an HDL mimetic structure on said C-m-HDLs”. From the teachings of the instant specification, it is understood that the acronym “C-m-HDLs” is meant to abbreviate the phrase “chemotherapeutic micellular HDL” as recited in para[0003], pg. 1. However, the claim recites that the amphiphilic, alpha-helical peptide or protein is an HDL mimetic structure. The Examiner is interpreting the term HDL mimetic structure as a synthetic peptide with diverse chemical modifications that imitates the structure and function of a natural high density lipoprotein (HDL). Therefore, the claim recitation “i) an amphiphilic, alpha-helical peptide or protein wherein said peptide or protein is an HDL mimetic structure on said C-m-HDLs” is ambiguous because it has not been clearly established whether the claimed population of chemotherapeutic micellular high density lipoproteins (i.e., C-m-HDLs) comprises a combination of unmodified HDLs and synthetic HDLs with modifications (i.e., HDL mimetic structure) or whether only HDL mimetic structures make up the claimed population of C-m-HDLs.
2. Claims 1-15, duplicate 15 (i.e., renumbered claim 16) and 19 (i.e., renumbered claim 20) 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 1 recites that the claimed population of C-m-HDLs comprises: “iii) a conjugate comprising an anchor moiety molecule and paclitaxel is releasably attached to each other through a cleavable bond”. However it has not been clearly defined what structures, other than the anchor moiety, constitute the conjugate. The claim as recited, in particular the phrase attached to each other indicates that the conjugate is formed by an anchor moiety, paclitaxel in addition to a third structure; but if a third structure is present, it is unclear what that structure is. The claim fails to clearly recite which structures form the conjugate.
4. Claims 10 and 14 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. The claims recite that the terms “plus/minus about” before a numerical designation such as average particle size. However, an ordinary skilled artisan would not be able to ascertain the metes and bounds of the C-m-HDLs with respect to the average particle diameter because the terms “plus/minus” and “about” when used together to refer to the same numerical designation renders the claim ambiguous and/or unclear. The instant specification teaches that the term “about” indicates approximations that may vary by plus (+) or minus (-) 10%, 5%, 1% or any subrange or any sub value therebetween (see pg. 34, para[0099]). However, claim 10 recites “plus/minus about 3 nanometers” and claim 14 recites “plus/minus about 2 nanometers”. Therefore, the use of both terms causes confusion because it is understood that 3 nanometers (i.e., in claim 10), and 2 nanometers (i.e., in claim 14) refer to the subrange or sub value therebetween 10% and 1% that varies in the average particle diameter (i.e., numerical designation); instead of indicating that the reference value for the average particle diameters are 3 nanometers and 2 nanometers.
5. Claim 15 is 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 15 recites that the paclitaxel-anchor moiety is selected from a conjugate of Table 6. MPEP 2173.05(s) states that [w]here possible, claims are to be complete in themselves and that incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. In the instant case, claim 15 is indefinite because the contents of Table 6 is not incorporated in the claim. Table 6 depicts 14 paclitaxel-carbonate conjugates that can be incorporated as part of the claim limitation to further narrow the parent claim. Applicant may amend the claim by incorporating Table 6 as part of the claim instead of incorporating the contents by reference.
6. Claims 15 (i.e., renumbered claim 16) is 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. The claim recites the limitation “… ß-, γ-, and δ-tocotrienol or ß-, γ-, and δ-tocopherol” in line 2. An ordinary skilled artisan would not be able to ascertain the metes and bounds of the claimed invention with respect to the anchor moiety because renumbered claim 16 recites that the anchor moiety is “… ß-, γ-, and δ-tocotrienol or ß-, γ-, and δ-tocopherol.” From reading the quoted limitation, it is understood that the tocotrienol moiety is a combination of the three isomers (i.e., beta, gamma and delta); the same is true for the ß-, γ-, and δ-tocopherol. For examination purposes, the Examiner will interpret that the anchor moiety is ß-tocotrienol or γ-tocotrienol or δ-tocotrienol or ß-tocopherol or γ-tocopherol or δ-tocopherol.
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.
7. Claims 1-15, 15 (i.e., renumbered claim 16) and 19 (i.e., renumbered claim 20) are 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 claims 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.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus.
Independent claim 1 includes “…a population of C-m-HDLs, wherein said C-m-HDLs in said population comprise: i) an amphiphilic, alpha-helical peptide or protein, wherein said peptide or protein is an HDL mimetic structure on said C-m-HDLs; […] and iii) a conjugate comprising an anchor moiety molecule …” Likewise, independent claim 9 which is drawn to a population of C-m-HDLs includes “…(c) a conjugate comprising an anchor moiety molecule…” As such, the scope of the claimed “population of C-m-HDLs” encompasses any amphiphilic, alpha-helical peptide or protein that mimics the structure of HDL (i.e., claims 1-8); as well as any conjugate comprising any anchor moiety molecule (i.e., claims 1-15 and 20). Therefore, the scope of claims 1-8 and 9-15 encompass a vast array HDL mimetic structures and a vast array of conjugates comprising an anchor moiety molecule without a necessary core structure and/or sequence that would be needed for the population of C-m-HDLs to exhibit the claimed function of HDL mimetic micellular nanoparticles.
Applicant reduced to practice a total of 36 peptides, as shown in Table 7, suitable for use in the micellar nanoparticles (see instant specification, pg. 55, para[0187]); and a total of 84 conjugates as shown in tables 1-6 (see instant specification, pp. 6-20), with preferred conjugates illustrated in Figures 18A through 18N.
An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. MPEP 2163 (I)(A). The peptides and conjugates reduced to practice (i.e., sequences listed in Table 7, and conjugates listed in tables 1-6) do not share a common core structure; without an indication of a core structure, sequence or residues that would be necessary in order for a population of C-m-HDL to exhibit the claimed function (i.e., HDL mimetic micellular nanoparticles), it would be difficult for a skilled artisan to envision the correlation between structure and function for the whole genus and/or to predict what would be covered by the functionally claimed genus because Applicants have failed to provide a representative number of species to support the scope of the whole genus.
The written description requirement may be met by provided a representative number of species of the genus and/or in light of the state of the art. With regard to the state of the art, Raut et al. report the design and characterization of actively targeted micelles using an amphipathic helical peptide, conjugated to a fatty acid molecule (see Raut et al. J. Pharmacology Exp Ther, 2020, 373:113-121, at pg. 119, Discussion). Raut’s HDL mimetic drug carrying nanoparticles which involve the macromolecular assembly of the myristic acid conjugated peptide (MYR-5A) into nano-micellular structures where the sequence DWLKAFYDKVAEKLKEAF-P-DWAKAAYDKAAEKAKEAA corresponding to 5A peptide, its predicted double helical structure and the schematic of myristic acid conjugated on the N-terminal of 5A peptide are shown (see pg. 114, Fig. 1).
Furthermore, Lacko et al. teach targeted drug delivery vehicle compositions and methods of manufacture, which involve a targeting amino acid chain bound to a biocompatible polymer, where the biocompatible polymer is a fatty acid or myristic acid (see Lacko et al. US20150343069A1, Pub. Date: Dec. 3, 2015 at pg. 1, para[0009]). Lacko et al. also teach that the targeting amino acid chain can have an affinity to membrane-bound receptors that are tissue, cell or organ specific (see pg. 4, para[0053]). For instance heparin binding site, integrin binding site, P-selectin, internalization sequence of TAT HIV, panning, penatratin, neural cholesterol esterase activation SAA C-terminus, inhibition of ACAT SAA N-terminus, increase liver affinity LDL receptor, anti-oxidant activity modified 18A, ApoA-I milano, heavy metal chelation 6x-His sequence, lactoferrin, and scavenger receptor type B-1 (SR-B1) binding sequences (see pg. 4, para[0054]). Also that in some embodiments the targeting amino acid chain has an affinity to an HDL receptor (see pg. 1, para[0010]). Additionally, Lacko teaches that the targeting amino acid chain can comprise one or more alpha helix (see pg. 3, para[0042]); and can also have amipathic properties (see pg. 4, para[0049]). For instance, a targeting amino acid chain can have a hydrophilic property on one side of the alpha helix and has a hydrophobic property on the opposite side of the alpha helix (see pg. 4, para[0049]).
Therefore, Raut’s and Lacko’s teachings present compelling evidence stablishing the structure and function of micelles and/or drug delivery compositions which comprise a peptide that mimics HDL and a conjugate comprising a lipid (i.e., myristic acid). Thus, the instantly claimed invention is directed to a population of C-m-HDLs with a certain function but no correlated structure associated with that function. Without such structure, the specification does not convey possession of the breadth of the claimed genus.
Alternatively, the written description requirement may be met by providing a representative number of species of the genus. In the instant case, the specification teaches Examples 1-4 and 11, which describe the synthesis of conjugates 20, 40, 50, 60 and 70 (see instant specification, pp. 70-72 and pg. 78). As well as, Example 15 and Fig. 13 which describe C-m-HDLs made with different peptides (i.e., SEQ ID NOs: 25, 35 or 37) (see instant specification, pg. 83, para[0289]) and Fig. 13). Thus, evidence of a handful of positive integrant and replicative experiments of only three peptides (i.e., SEQ ID NOs: 25, 35 or 37) and five conjugates is not sufficient for the skilled artisan to envisage what constitutes a necessary core structure and/or sequence that would preserve function.
Therefore, claims 1-15, 15 (i.e., renumbered claim 16) and 19 (i.e., renumbered claim 20) do not meet the written description requirement.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
8. Claims 1, 3-6 and 8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2011/0020242 A1 Pub. Date: Jan. 27, 2011 (herein after “Zheng et al.”).
For claim 1, Zheng et al.’s invention discloses pharmaceutical formulations comprising HPPS (High-Density Lipoprotein-like peptide phospholipid scaffold) nanoparticles and methods of making the HPPS nanoparticles (see Abstract); thereby corresponding to a composition comprising a population of HDL mimetic micellular nanoparticles, as recited in instant claim 1. Zheng et al.’s pharmaceutical compositions comprise pharmaceutically acceptable carriers well known in the art such as water and carbohydrates such as glucose or sucrose (see pg. 11, para[0160]); thereby corresponding wherein the composition comprises water and a disaccharide, as recited in instant claim 1. Zheng et al.’s HPPS comprise (a) at least one phospholipid, (b) at least one unsaturated lipid, preferably an unsaturated sterol ester, further preferably an unsaturated cholesterol ester, further preferably cholesteryl oleate; and (c) at least one peptide, the peptide comprising an amino acid sequence capable of forming at least one amphipathic α-helix; wherein the components a), b) and c) associate to form the peptide-phospholipid nano scaffold (see Abstract); thereby corresponding wherein the population of HDL mimetic micellular nanoparticles comprises an alpha-helical peptide, a sphingomyelin as recited in i) of instant claim 1. Zheng et al.’s Figure 1 illustrates a HPPS nanoparticle that allow targeted delivery of active agents for the detection and treatment of cancers and other diseases(see pg. 3, para[0061]), where it can be seen that the particle size ranges from approximately 5-25 nm, the core loading comprises a drug (e.g., paclitaxel) (see Fig. 1). Zheng et al. further disclose that paclitaxel docosahexaenoic acid (DHA)-paclitaxel conjugates are examples of anti-cancer drugs (see pg. 8, para[0127]), thereby corresponding to a conjugate comprising an anchor moiety molecule and a paclitaxel as recited in iii) of instant claim 1. Additionally, Zheng et al.’s lipoprotein particles consist of a core of hydrophobic lipids surrounded by a shell of more polar lipids and proteins (see pg. 4, para[0078]), thereby corresponding to wherein the C-m-HDLs comprise a hydrophilic exterior surface and a hydrophobic core, as recited in instant claim 1. Zheng et al.’s Fig. 1 illustrates that the HPPS nanoparticles comprise amphipathic size-control peptides (scPep) and phospholipids which form an ultra-small nanocarrier (5 to 25 nm) (see Fig. 1 and pg. 3, para[0061]); thereby corresponding to wherein the C-m-HDLs in the population have an average particle diameter of from about 11.5 nanometers to about 14 nanometers, as recited in instant claim 1. MPEP 2131.03 (I) states that a specific example in the prior art which is within a claimed range anticipates the range, "[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art." Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). As such the disclosure of Zheng anticipates the claim limitations recited in instant claim 1.
For claim 3, Zheng et al.’s Fig. 1 discloses that the particle size to be 5-25nm (see Fig. 1), additionally, Zheng et al. disclose that the non-naturally occurring HPPS nanoparticles are (in increasing preferability) from 5 nm to 50 nm in diameter, from 5 nm to 40 nm in diameter; from 5 nm to 30 nm in diameter, from 5 nm to 25 nm in diameter; from 5 nm to 20 nm in diameter, and from 10 nm to 15 nm in diameter (see pg. 5, para[0090]; thereby corresponding to wherein said C-m-HDLs in said population have an average particle diameter of from about 12 nanometers to about 13.5 nanometers, as recited in instant claim 3.
For claims 4-5, Zheng et al.’s pharmaceutical compositions comprise a pharmaceutically acceptable carrier which can contain physiologically acceptable compounds that act, for example, to stabilize or to increase the absorption of the complex (see pg. 11, para[0161]). For instance physiologically acceptable compounds include, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients (see pg. 11, para[0161]). Thereby corresponding to wherein said disaccharide is selected from sucrose, lactose, maltose, trehalos, cellobiose and lactulose as recited in instant claim 4; and corresponding to wherein said disaccharide is sucrose as recited in instant claim 5.
For claims 6 and 8, Zheng discloses that the nanoplatforms may be provided in a physiologically or pharmaceutically acceptable carrier, or may be provided in a lyophilized form for subsequent use (see pg. 11, para[0162]); thereby corresponding to a lyophilized composition of the composition of claim 1, as recited in instant claim 6; and corresponding to a lyophilized composition of the composition of claim 3, as recited in instant claim 8.
9. Claims 1-3 and 6-8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 10,532,105 B2. Date of Patent: Jan. 14, 2020 (herein after “Homan et al.”).
For claim 1, Homan et al. disclose Example4 which describes the preparation of peptide amphiphile lipid micelle (PALM) (see column 32, lines 16-18); thereby corresponding to composition comprising a population micellular nanoparticles, as recited in instant claim 1. Homan et al. prepared separate stocks solutions of peptide and phospholipids in a solvent mixture composed of 80% tert-butyl alcohol (TER) and 20% water to obtain separate solutions of 10 mM peptide, 20mM 1,2-dioleoyl-snglycero-3-phosphocholine (DOPC) or 20 mM l-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) and 20 mM egg SM (sphingomyelin) (see column 32, lines 19-24); thereby corresponding to i) an amphiphilic, alpha helical peptide, and ii) one or both of sphingomyelin and phosphatidyl choline as recited in instant claim 1. Homan et al.’s Example 4 also discloses that a visual clear preparation indicated any nanoparticles that had formed were less than approximately 20 nm diameter (see column 32, lines 64-66). MPEP 2131.03 (I) states that a specific example in the prior art which is within a claimed range anticipates the range. As such, Homan et al.’s Example 4 anticipate the claim limitations recited in instant claim 1, wherein the average particle diameter of from about 11.5 nm to about 14 nm.
Homan et al. also disclose Example 8, which describes the preparation of PALM containing paclitaxel δ-tocotrienyl carbonate (see column 34, Example 8, lines 4-7). Since the instant specification teaches that an “anchor moiety” refers to the lipid portion of a chemotherapeutic conjugate (see instant specification, pg. 36, para[00107]); Homan et al.’s paclitaxel δ-tocotrienyl carbonate corresponds to a conjugate comprising an anchor moiety and paclitaxel, as recited in instant claim 1. Homan et al. also disclose that the particle size is measured by DLS and that the nano-meter sized particles have a mean diameter of 30 nm or less, or from about 10 nm to 30nm (see column 14, lines 31-5 and lines 38-40); thereby corresponding to wherein the population has an average particle diameter of from about 11.5 nm to about 14 nm as measured by dynamic light scattering, as recited in instant claim 1.
Regarding wherein the claimed composition comprises a population of micelles are HDL mimetic micellular nanoparticles; wherein the conjugate is releasably attached to each other through a cleavable bond; and wherein the C-m-HDLs in the population comprise a hydrophilic exterior surface and a hydrophobic core, as recited in instant claim 1. Pursuant to MPEP 2112.01 (II), "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Since Homan et al.’s disclose peptide amphiphile lipid micelle (PALM) which comprises an amphiphilic alpha-helical peptide (see column 2, line 45), water, 1,2-dioleoyl-snglycero-3-phosphocholine (DOPC) or 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) and SM (sphingomyelin) as well as paclitaxel δ-tocotrienyl carbonate; it must follow that Homan et al.’s PALM also exhibits the instantly claimed properties (i.e., HDL mimetic micellular nanoparticles, conjugate that is releasably attached to each other through a cleavable bond; and C-m-HDLs comprising a hydrophilic exterior surface and a hydrophobic core).
For claim 2, Homan et al. claim that the peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 3-35 (see column 82, claim 2 and Table 2, column 9, line 15). It is noted that Homan et al.’s SEQ ID NO: 35 is 100 % identical to instant SEQ ID NO: 35 (i.e., Applicant’s elected species) DVFQKLXELFNQLXEKWKQV where the residues at positions 7 and 14 is Aib.
For claim 3, as previously discussed, Homan et al.’s Example 4 discloses that a visual clear preparation indicated any nanoparticles that had formed were less than approximately 20 nm diameter (see column 32, lines 64-66). MPEP 2131.03 (I) states that a specific example in the prior art which is within a claimed range anticipates the range. As such, Homan et al.’s Example 4 anticipate the claim limitations recited in instant claim 3, wherein the average particle diameter of from about 12 nm to about 13.5 nm.
For claims 6-8, Homan et al. disclose lyophilizing the peptide/sphingomyelin/phospholipid/cargo molecule solution, wherein the solvent mixture comprises tert-butyl alcohol and water (see column 29, lines 4-6).
Accordingly, Homan et al.’s disclosure anticipates instantly claimed limitations recited in claims 1-3 and 5-6.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness
(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
10. Claims 9-15, 15 (i.e., renumbered claim 16) and 19 (i.e., renumbered claim 20) are rejected under 35 U.S.C. 103 as being unpatentable over US 2011/0020242 A1 Pub. Date: Jan. 27, 2011 (herein after “Zheng et al.”), in view of US 10,532,105 B2 Date of Patent: Jan. 14, 2020 (herein after “Homan et al.”), Stjerndahl et al., J Surfact Deterg (2019) 22: 1139-1145 (herein after “Stjerndahl et al.”), and WO 00/59492 International Publication Date: Oct. 12, 2000 (herein after “Fariss et al.”)
Regarding claim 9, Zheng et al. teach pharmaceutical formulations comprising HPPS (High-Density Lipoprotein-like peptide phospholipid scaffold) nanoparticles and methods of making the HPPS nanoparticles (see Abstract). Zheng et al.’s HPPS nanoparticles contain anticancer agents, and such agents can be a chemotherapeutic agent (see pg. 4, para[0073]); thereby constituting a population of C-m-HDLs, as recited in instant claim 9. Zheng et al. claim that the non-naturally occurring peptide-lipid nano scaffold comprises at least one peptide, the peptide comprising an amino acid sequence capable of forming at least one amphipathic α-helix (see pg. 21, claim 1), thereby constituting an amphiphilic, alpha-helical peptide or combinations thereof wherein said peptide forms an HDL mimetic structure on said nanoparticle. Zheng et al. use the term “peptide” broadly to mean peptides, polypeptides, proteins and fragments of proteins and includes single-chain peptides and other molecules such as peptoid, peptidomimetics and the like (see pg. 7, para[0111]). Examples of small amphipathic helix peptides, possessing many of the lipid binding properties of apoA-1 include 2F, an 18-amino acid peptide sequence with two phenylalanine amino acid residues (D-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F) (see pg. 6, para[0100]). Zheng et al. add that early studies showed that this sequence displayed strong lipid association and was able to form stable discoidal phospholipid particles (see pg. 6, para[0100]). Additionally, that subsequent studies went on to show that the incorporation of two additional F residues further enhanced the lipid associating properties of the peptide (see pg. 6, para[0100]).
However, Zheng et al. do not expressly teach an amino acid sequence of any one of SEQ ID NOs: 25, 28, 34, 35, 36 or combinations thereof as recited in instant claim 9.
Homan et al. teach peptide amphiphile lipid micelles, process for making them and optionally comprising a cargo molecule (see abstract). Homan et al.’s Table 2 depicts particular peptides of the invention, such as peptide sequence DVFQKL{AIB}ELFNQL{AIB}EKWKQV identified with SEQ ID NO: 35 (see column 9, line 35). Homan et al.’s SEQ ID NO: 35 is 100% identical to instant SEQ ID NO: 35 (i.e., Applicant’s elected species). Homan et al. also teach the amphiphilic peptides are able to adopt an alpha helical conformation in which the helix has opposing polar and non-polar faces oriented along the long axis of the helix (see column 5, lines 66-67 and column 6, lines 1-4). Additionally, Homan et al.’s Table 1 depicts the charge distribution of specific amphiphilic peptides where it can be appreciated that SEQ ID NOs: 24-35 have zero charge at the positions 7 and 14 (see columns 5-6, Table 1, second entry and footnotes). Homan et al. teach Fig. 9, which depicts PALM prepared with various peptides as indicated, and containing Dil, were incubated with BHK (SR-B1); the incubations were performed with un-induced (control) or induced cells (i.e., SR-B1 gene induced) and human HDL labeled with Dil (1,1'-dioctadecyl-3,3,3',3'tetramethylindocarbocyanine, see column 4, lines 56-57) was tested for comparison (see column 3, lines 45-46). Fig. 9, shows that the peptide with the highest pmol Dil/ug protein or peptide in induced cells was SEQ ID NO: 35 with 1.26+/- 6 pmol/ug/ml Dil uptake (see Fig. 9 and Table 6, column 35). As such, the teachings of Zheng et al. when combined with the teachings of Homan et al. are suggestive of the claim limitations as recited in claim 9 (a).
From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the 2F apoA-1 sequence of Zheng et al. with Homan et al.’s SEQ ID NO: 35 in order to arrive at a population of C-m-HDLs comprising an amphiphilic, alpha-helical peptide that comprises an amino acid sequence of SEQ ID NO: 35 (i.e., Applicant’s elected species), wherein said peptide forms an HDL mimetic structure on said nanoparticle. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because Homan et al.’s SEQ ID NO: 35 is 100% identical to instant SEQ ID NO: 35; and because the peptide amphiphile lipid micelles (i.e., PALM) prepared with SEQ ID NO: 35 exhibited the highest Dil uptake. One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that Homan et al.’s SEQ ID NO:35 was known; given that Zheng et al.’s HDL-like peptide-phospholipid scaffold (HPPS) nanoparticles comprises at least one peptide capable of forming at least one amphipathic α-helix; and given that the amphipathic helix peptides, possessing many of the lipid binding properties of apoA-1 include two phenylalanine amino acid residues (i.e., 2F) which display strong lipid association and are able to form stable discoidal phospholipid particles. Therefore, substituting Zheng et al.’s apoA-1 2F peptide with Homan et al.’s SEQ ID NO: 35 would support an amphiphilic, alpha-helical peptide that comprises SEQ ID NO: 35 and forms an HDL mimetic structure on said nanoparticle by constituting some teaching, suggestion or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Zheng et al. teach that the phospholipid of the peptide-lipid nano-scaffold is selected from phosphatidylcholine, POPC and EYPC (see pg. 21, claim 18), thereby constituting (b) one or both of sphingomyelin and phosphatidyl choline, and optionally additional lipid(s) or phospholipid(s), as recited in instant claim 9 (b).
Zheng et al. teach that pharmaceutically active lipophilic drugs which may be incorporated into targeted drug delivery complexes include drugs for the treatment of cancer (see pg. 8, para[0126]); such as docosahexaenoic acid (DHA)-paclitaxel conjugates (see pg. 9, para[0127]); thereby constituting (c) a conjugate comprising an anchor moiety molecule and paclitaxel as recited in instant claim 9. Zheng et al. add that cholesterol moieties may also be used to anchor other active agents within the core of the HPPS nanoparticles (see pg. 9, para[0137]). Such anchors may be covalently bound to active agents using synthetic methods known to those of skill in the art, and the anchors may also be covalently bound to the active agent via an ester linkage (see pg. 9, para[0137]), thereby constituting wherein the anchor moiety molecule and paclitaxel are releasably attached to each other through a cleavable bond, as recited in instant claim 9.
Zheng et al. teach that the starting materials of the HPPS nanoparticles contain at least one lipid that is on, for example, the outer surface layer of the particle and that lipids useful in the HPPS nanoparticles include, but are not limited to, amphipathic lipids. (see pg. 5, para[0091]). Additionally, that drug/probe sequestration in the lipid core space provides protection from serum enzyme and water (see pg. 5, para[0089]), thereby constituting wherein the micellular nanoparticles of the population have a hydrophobic core, as recited in instant claim 9. As such, if the HPPS nanoparticle includes amphipathic lipids, and if the lipid core provides protection form serum enzyme and water, it must follow that the nanoparticles have a hydrophilic exterior; thereby constituting wherein the micellular nanoparticles in the population have a hydrophilic exterior, as recited in instant claim 9.
Zheng et al. also teach that the non-naturally occurring HPPS nanoparticles are from 10 nm to 15 nm in diameter (see pg. 5, para[0090]); thereby constituting wherein the micellular nanoparticles in the population have an average particle diameter of from about 11.5 to about 14.0 nanometers, as recited in instant claim 9. Additionally, MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses by the prior art" a prima facie case of obviousness exists. Therefore, the claimed particle diameter range would have been obvious to one of ordinary skill in the art since the prior art range (i.e., 10nm to 15 nm) lies within the claimed 11.5 nm to about 14.0 nm.
Regarding claim 10, Zheng et al. teach Table 4, which indicates the proportion of the population of nanoparticles that have the indicated size (see pg. 15, Table 4). Table 4, displays the mean size, percent composition, where it can be appreciated that 99% of the particles had a mean size between 10.9nm and 13.7nm (see Table 4 at pg. 9); thereby constituting wherein at least 70% of said C-m-HDLs are within plus/minus about 3 nm of the average particle diameter, as recited in instant claim 10.
Regarding claim 11, as previously mentioned, Zheng et al. teach that cholesterol moieties may be covalently bound to active agents using synthetic methods known to those of skill in the art, and the anchors may also be covalently bound to the active agent via an ester linkage (see pg. 9, para[0137]); thereby constituting wherein the releasable bound is an ester, as recited in instant claim 11.
Regarding claim 12, Zheng et al. teach that suitable anchors for active agents include oleate and unsaturated cholesterol ester moieties (see pg. 9, para[0137]). Such anchors may be covalently bound to active agents using synthetic methods known to those of skill in the art (see pg. 9, para[0137]). The anchors may be covalently bound to the active agent via an ester linkage (see pg. 9, para[0137]). However, Zheng et al. do not expressly teach wherein the releasable bond is a carbonate bond as, recited in instant claim 12.
Homan et al. teach that the PALM-cargo molecule complex is a compound conjugate of formula (I) i.e., A-R-L-X (see column 15, lines 31-35); wherein A is an agent having an hydroxy or amine group and wherein R is a hydroxy group or amine group of the agent, and the anchor moiety is covalently bonded to agent by a carbonate ester bond (see column 16, lines 6-7); thereby constituting wherein the releasable bond is a carbonate bond. Additionally, Homan et al. teach that the agent is an anticancer drug covalently bonded to the anchor by a carbonate ester bond (see column 16, lines 27-29); for instance the cargo molecule is paclitaxel 2'-cholesteryl carbonate (see column 16, lines 43-45).
Stjerndahl et al. are in the field of cleavable surfactants and teach a comparison between ester, amide and carbonate as the weak bond (see pg. 1139, Title). In particular, Stjerndahl et al. compare the physical-chemical properties and degradation characteristics of three types of surfactants: amphiphiles with either amide, carbonate, or ester (“normal ester”) as hydrolysable linkage between the polar headgroup and the hydrophobic tail (see pg. 1140, right column, paragraph 3). Stjerndahl et al. teach Table 1, which depicts the physical-chemical properties as well of half-lives of the cleavable surfactants; where it can be appreciated that the critical micelle concentration (CMC) and cloud point (CP) values of the carbonate surfactant are the lowest and the carbonate bond is more unipolar than the ester bond and it is also more stable to alkaline hydrolysis than an ester bond (see pg. 1141, right column, paragraph 1). Stjerndahl et al. conclude that surface-active molecules with a carbonate bond between the hydrophobic tail and the polar headgroup are of interest as cleavable surfactants, particularly when one wants to avoid acidic degradation products (see pg. 1145, left column, paragraph 2). Judging from values of the CMC and CP, a carbonate linkage is somewhat less hydrophilic than an ester bond and it is slightly more stable to alkaline hydrolysis than an ester bond (see pg. 1145, left column, paragraph 2).
From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the ester linkage between the lipid anchors and the active agent of Zheng et al. with the carbonate ester bond of Homan et al. in order to arrive at the claimed population of C-m-HDLs wherein the releasable bond is a carbonate bond. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because the physical and chemical properties of cleavable surfactants with carbonate or ester hydrolysable linkage between the polar headgroup and the hydrophobic tail were known; because it was also known that the carbonate bond is more unipolar than the ester bond and it is also more stable to alkaline hydrolysis than an ester bond as taught by Stjerndahl et al. One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that the PALM-cargo molecule complex is a conjugate of an agent (i.e., paclitaxel) and an anchor moiety covalently bonded by a carbonate ester bond as taught by Homan et al. Therefore, substituting Zheng et al.’s ester linkage between the lipid anchors and the active agent with Homan et al.’s carbonate ester bond would support a population of C-m-HDLs wherein the releasable bond is a carbonate bond by constituting some teaching, suggestion or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Regarding claim 13, as previously mentioned, Zheng et al. teach that the non-naturally occurring HPPS nanoparticles are from 10 nm to 15 nm in diameter (see pg. 5, para[0090]); thereby constituting wherein an average particle diameter of from about 12 to about 13.5 nanometers, as recited in instant claim 13. MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses by the prior art" a prima facie case of obviousness exists. Therefore, the claimed particle diameter range would have been obvious to one of ordinary skill in the art since the prior art range (i.e., 10nm to 15 nm) lies within the claimed 12 nm to about 13.5 nm.
Regarding claim 14, as previously mentioned, Zheng’s Table 4, displays the mean size, percent composition, where it can be appreciated that 99% of the particles had a mean size between 10.9nm and 13.7nm (see Table 4 at pg. 9); thereby constituting wherein at least 70% of said C-m-HDLs are within plus/minus about 2 nm of the average particle diameter, as recited in instant claim 14.
Regarding claims 15 and 15 (i.e. renumbered claim 16), Zheng et al. teach that at least one active agent is bound to at least one lipid anchor (see pg. 21, claim 25). Additionally, Zheng et al. teach docosahexaenoic acid (DHA)-paclitaxel conjugates (see pg. 9, para[0127]). However, Zheng et al. do not expressly teach wherein the paclitaxel-anchor moiety is moiety No. 78 , i.e., P