DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the AIA .
Claims Status
Claims 1-8 are pending and under current examination in this application.
Claim Rejections - 35 USC § 112(b)
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 Applicant regards as his invention.
Claims 1-8 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, regards as the invention.
The phrase “cationic hydrophobic block portion” in claims 1 and 2 is unclear and internally inconsistent. Cationic polymers are generally hydrophilic due to charge solvation in aqueous environments, whereas hydrophobic polymers are typically uncharged. The claims do not explain how the block is simultaneously cationic and hydrophobic, nor do they define a measurable parameter or structural feature that resolves this ambiguity. Dependent claims 3-8 are also included in this rejection because they do not cure the defect noted above.
In claim 1, the phrase “crosslinking block portion positioned between the hydrophilic block and the cationic hydrophobic block” is ambiguous. It is unclear whether this refers to a discrete polymer block, a functionalized segment, or a region formed only after crosslinking. The claims do not specify whether the crosslinking block exists prior to micelle formation or is generated during assembly. Dependent claims 2-8 are included in this rejection because they do not cure the defect noted above.
Claim 7 fails to specify how net charge is measured, calculated, or averaged (e.g., per molecule, per chain length, per formulation). Because net charge depends on molecular length, counterions, and measurement conditions, this limitation renders the scope of the claim indefinite.
To overcome these rejections, the Applicant may amend the claims or specification to provide clarity to the phrases and specify how net charge is determined.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. § 102 and 103 (or as subject to pre-AIA 35 U.S.C. § 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1, 2, and 5-8 are rejected under 35 U.S.C. § 103 as being unpatentable over Breitenkamp et al. (WO2006107903A2; published 12 October 2006, hereinafter referred to as “Breitenkamp”) in view of Kataoka et al. (Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv Drug Deliv Rev. 2001 Mar 23;47(1):113-31; hereinafter referred to as “Kataoka”).
Breitenkamp teaches teaches micelles comprising multiblock copolymers having a hydrophilic block (shell) and other polymer blocks forming a micellar core where drugs are encapsulated as, “…micelle[s] comprising a multiblock copolymer which comprises a polymeric hydrophilic block, a crosslinked poly(amino acid block), and a poly(amino acid block), characterized in that said micelle has an inner core, a crosslinked outer core, and a hydrophilic shell…characterized in that said micelle has a drug-loaded inner core…” (¶[0033]), wherein “…the terms "drug-loaded" and "encapsulated", and derivatives thereof, are used interchangeably…. "drug-loaded" micelle refers to a micelle having a drug, or therapeutic agent, situated within the core of the micelle. This is also referred to as a drug, or therapeutic agent, being "encapsulated" within the micelle.” (¶[0041]).
Figure 1 and ¶[0007] of Breitenkamp depicts and describes core crosslinked, shell crosslinked, and outer-core crosslinked micelles. Crosslinking inherently requires at least two polymer chains. A skilled artisan would understand that to crosslink a micelle's core or shell, multiple copolymer chains within the assembly must be covalently linked. Breitenkamp also teaches polymer micelles wherein the cationic core is formed by the assembly of multiple cationic core-forming block copolymer chains (¶[0023]), thus the architecture of two chains contributing to a shared hydrophilic shell and a shared core where at least one chain is cationic would thus be an integral structure of any crosslinked micelle formed from multiple amphiphilic copolymer chains.
Breitenkamp describes the polymeric micelles with an outer core that is crosslinked and provides multiple crosslinking chemistries including exemplary pH-reversible hydrazone crosslinks (¶[0011], ¶[0012], and Drawing Figures 5 and 6). Breitenkamp expressly discloses hydrazone crosslinking schemes for micelles by reacting functional groups with hydrazine/hydrazide linkers to form hydrazone bridges as, “…drug loaded micelles possessing aldehyde or ketone functionality … crosslinked … to form pH-reversible hydrazone crosslinks.” (¶[00296]). In Breitenkamp, the hydrazone crosslinks are formed between functional groups on multiple multiblock polymer chains, effectively linking them in the outer core region (see hydrazone reactions in Drawing Figures 5 and 6 showing bifunctional linkages between polymer moieties).
Breitenkamp broadly teaches the concept of micelles encapsulating ionic therapeutic agents (¶[0031]) and states, “Polymer micelles with cationically charged, core-forming blocks are used to encapsulate biomolecules such as plasmid DNA and siRNA. Therapeutics of this type are normally susceptible to rapid in vivo degradation, and their encapsulation in polymer micelles improves their biodistribution profiles thus leading to future clinical successes.” (¶[0023]). Thus, describing a poly-ion complex micelle with a cationic block for anionic drugs.
Breitenkamp also discusses block copolymers with hydrophilic (e.g., PEG) and hydrophobic portions forming core-shell micelles (¶[0022]), and the ability to tune the core for drug encapsulation (¶[0023]). While Breitenkamp teaches a generic multiblock micelle with a crosslinked outer core, Breitenkamp does not explicitly teach the specific architecture of a cationic hydrophobic block tailored for electrostatic complexation with anionic drugs.
Breitenkamp discloses multiblock polymers (e.g., W-X′-X″ format; ¶[0036]-[0040]) where polymer blocks may contain ionic blocks (¶[0032]) hydrophobic regions (¶[0043]), which can include polylysine. A crosslinked poly-ion complex micelle core, as taught in Breitenkamp (¶[0023] and Drawing Figure 1), would be formed from the assembly of multiple copolymer chains. While not explicitly cationic, charged groups or ionic agents/blocks are contemplated as, “…micelle comprising a multiblock copolymer which comprises a polymeric hydrophilic block, a crosslinked poly(amino acid block), and a poly(amino acid) block…” (¶[0076]). If the core is cationic and crosslinked, it is then logical for both contributing chains to possess a cationic block to participate in drug complexation and core formation. A cationic hydrophobic block portion further comprising a second cationic hydrophobic block of the second block copolymer chain is thus an obvious design for a crosslinked poly-ion complex micelle core. Using only one cationic chain in a crosslinked pair would be an inefficient and non-obvious deviation from standard polymer assembly. However, Breitenkamp does not explicitly teach the cationic hydrophobic block portion further comprising the second cationic hydrophobic block of the second block copolymer chain.
Kataoka teaches the design of poly-ion complex micelle from block copolymers such as PEG-poly(amino acid) block copolymers where the poly(amino acid) block can be cationic (e.g., polylysine) for DNA loading, wherein block copolymers with two charged segments increase electrostatic interactions with anionic therapeutics (e.g., DNA (page 123, section 7, first and second paragraph). This establishes the basic concept of using cationic block copolymers for anionic cargo as known in the art.
Breitenkamp teaches micelles of the present invention are about 20 to about 200 nm in diameter (¶[0022]), thus encompassing the instant claim 6 20-100 nm particle size and Kataoka teaches micelles having a polydispersity determined from cumulant analysis of DLS data is as low as 0.03, indicating the very narrowly distributed nature of the micelles (section 4, second paragraph and Figure 5), a micelle as small as 80 nm, with moderate polydispersity (section 7, first paragraph) and poly-ion complex micelles having a diameter of 149.0 nm, with a polydispersity index of 0.19” (section 8, second paragraph), thus encompassing the 0.05-0.3 PDI of instant claim 6. The size range is explicitly disclosed and overlaps with the claimed range and achieving a low PDI is an ordinary goal in nanoparticle synthesis and represents a predictable result of standard result of routine optimization of polymer length and assembly conditions.
Breitenkamp explicitly teaches wherein the micelle encapsulates a DNA plasmid, a microRNA (miRNA), an antisense RNA, or other RNA-based therapeutic (claim 36), thus directly teaching the limitation of instant claim 8, wherein plasmid DNA and RNA are polyanions with a high negative charge, which inherently can possess a net negative charge of −25 to −1 at a physiological pH (e.g., DNA or RNA plasmids of <25 nucleotides). Small molecule anionic drugs (e.g., nucleotide analogs like gemcitabine triphosphate) also fall within this charge range. The claimed charge range merely quantifies the inherent electrostatic character of the anionic drugs already taught by Breitenkamp. No unexpected result is linked to this range.
Further, Kataoka teaches, “the stability of PIC micelles becomes a critical issue from the standpoint of their utility as vehicles in the targeted delivery of DNA with considerably lower molecular weight, i.e., antisense oligo-DNA. There are several reports on the stabilization of the polymeric micelle by cross-linking of the core or the shell. In these cases, the cross-linkage fixed the structure of the micelle and permanently suppressed the dissociation. For application in drug delivery systems, however, the micelle must dissociate to release the entrapped drugs at the targeted site. To this end, cross-linking by reversible bonds is a promising method if the bond is cleaved in response to physical or chemical stimuli given in the environment at the site of drug action.” (pages 126-127, section 9, first paragraph), wherein antisense oligo-DNA is anionic and a standard therapeutic antisense oligo-DNA would be expected to fall within the range of having a -25 to -1 net charge (e.g., <25 nucleotides; 16-20mer antisense oligo-DNA would be expected to have a net charge of -20 to -16 at physiological pH). Thus, poly-ion complex micelles encapsulation of anionic nucleic acids with net negative charge, with ranges overlapping claim scope are taught by Kataoka.
Thus, Breitenkamp teaches creating a stable, crosslinked poly-ion complex micelle for drug delivery and explicitly teaches using cationic blocks to encapsulate anionic biomolecular drugs (e.g., siRNA) and using hydrazone chemistry as a method to crosslink micelles and it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to use the standard block PEG-polycation copolymer architecture to form poly-ion complex micelles taught by Kataoka in the invention of Breitenkamp. Thus, while the specific second cationic block is not explicitly taught in Breitenkamp, it would be obvious to a skilled artisan to modify the multiblock polymer design for enhanced ionic complexation.
One of skill in the art would understand Breitenkamp’s poly(amino acid) blocks can include polylysine segments used for cationic blocks in micelles for anionic drug complexation, which is further shown to be a known cationic block for forming poly-ion complex micelles with nucleic acids by Kataoka. The use of polylysine is a routine selection for the cationic block function taught by Breitenkamp. It is the classic, and would be an obvious choice for a skilled artisan designing a poly-ion complex micelle from the combined teachings of Breitenkamp and Kataoka.
One would be motivated to combine these teaching to stabilize a poly-ion complex micelle, as taught by Kataoka, against dissociation using the crosslinking techniques of Breitenkamp. Selecting hydrazone crosslinking from the options detailed by Breitenkamp is a predictable choice, known for its pH sensitivity. The resulting structure where crosslinked chains form a shared shell and core is the inevitable product of crosslinking the pre-assembled micelle taught by the combined references.
Claims 1, 3 and 4 are rejected under 35 U.S.C. § 103 as being unpatentable over Breitenkamp et al. (WO2006107903A2; published 12 October 2006, hereinafter referred to as “Breitenkamp”) in view of Kataoka et al. (Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv Drug Deliv Rev. 2001 Mar 23;47(1):113-31; hereinafter referred to as “Kataoka”) in further view of Qi et al. (Hydrazone-Containing Triblock Copolymeric Micelles for pH-Controlled Drug Delivery. Front Pharmacol. 2018 Jan 23;9:12; hereinafter referred to as “Qi”).
Breitenkamp and Kataoka teach the limitations of instant claim 1, as discussed above, from which instant claims 3 and 4 depend, however does not teach specific limitations of instant claims 3 and 4.
Breitenkamp teaches multiblock copolymers of formulae expressing hydrophilic, poly(amino acid) blocks and crosslinkable moieties, and defines multiblock polymers with segments designated for shell, outer core, and inner core, as described above. Breitenkamp teaches triblock architectures (A-B-C) with a hydrophilic PEG block (A), a functional middle block (B, which can be crosslinked), and a core-forming block (C, which can be cationic) (¶[0022-0025]). Thus, the instant claimed formulas cover standard triblock architectures where "A" is a hydrophilic unit (e.g., PEG), "B" is a crosslinkable unit, and the cationic block is a core-forming unit. This architecture is depicted by Breitenkamp (Drawing Figure 1, outer-core crosslinked) and standard for functional micelles.
Kataoka teaches PEG-poly(amino acid) block copolymers where the poly(amino acid) block can be cationic (e.g., polylysine) (page 120, section 5, paragraph 1).
Qi teaches triblock copolymers architectures incorporating hydrazone bonds between blocks in polymeric micelles (page 5, Figure 2). The instant claimed substituents and linkers are consistent with general polymer design taught by Qi.
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to use the specific structural formulas describing block order and repeating units of instant claims 3 and 4 in the invention of Breitenkamp given the generic multiblock polymer teachings of Breitenkamp combined with polymer design principles of Kataoka and examples incorporating hydrazone linkers of Qi. One would be motivated to do as a matter of routine experimental optimization with a reasonable expectation of success to make a change, since the specific design components were known at the time of the invention for the same purpose.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to REBECCA L. SCOTLAND whose telephone number is (571) 272-2979. The examiner can normally be reached M-F 9:00 am to 5:00 pm EST.
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/RL Scotland/
Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615