DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08/25/2025 has been entered.
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 .
Response to Amendment
Applicant’s response of 08/25/2025 has been received and entered into the application file. Claims 1-14, 20, 22-26, 28-31, 33-49, and 51-52 are pending in this application. New claim 52 is added.
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.
Claims 1-14, 20, 22-26, 28-31, 33-49 and 51-52 are rejected under 35 U.S.C. 103 as being unpatentable over Slager et al. (US 8,883,208 B2, 2014), Schneider et al. (Applications of EVA in drug delivery systems, Journal of Controlled Release, 2017), and Bilban et al. (WO 2013/017656 A1), and Wang et al. (Drug Delivery Implants in the Treatment of Vitreous Inflammation, Hindawi, 2013), and Almarsson et al. (US 2018/0085474 A1) further evidenced by MatWeb (Overview of materials for EVA, Film Grade, Website established 2011) and Alshetaili et al. (Hot Melt Extrusion Processing Parameters Optimization, processes, 2020).
Slager et al. teach devices and methods for the release of nucleic acid complexes. The delivery particle can include a polymeric matrix including a polyethyleneglycol containing copolymer and a nucleic acid complex disposed within the polymeric matrix. The nucleic acid complex can include a nucleic acid and a carrier agent. The invention includes implantable medical device comprising nucleic acid complex within a polymeric matrix (Abstract). Suitable polymers include poly(ethylene-co-vinyl acetate) having vinyl acetate concentrations of between about 10% and about 50% (col 19, lines 34-36). Slager et al. teach the multi-block polymers can have temperature of approximately 37 degrees Celsius (col 7, lines 1-3).
Slager et al. do not specifically mention the ratio of the melting temperature of the carrier to the ethylene vinyl acetate copolymer.
Schneider et al. teach that ethylene vinyl acetate (EVA) is used in many drug delivery systems (Table 1, and Introduction paragraph). Schneider et al. teach that crystallinity, melting point, stiffness and polarity of the EVA is determined predominantly by the VA content. EVA at zero VA content has a melting temperature range of 110-120 degree Celsius. Melting temperature of EVA decreases with increasing VA concentration, leading to an amorphous, soft polymer with a broad melting point of 45-55 degree Celsius at 40 wt.% vinyl acetate (page 285, Properties of EVA).
Neither Slager or Schneider explicitly mention ribonucleic acid degradation inhibitor.
Bilban et al. teach antagonists of a ribonuclease being a member of the RNAse A family for use in treating diseases associated with obesity and the like (Abstract). Preferably, the antagonists are miRNA, dsRNA, siRNA, shRNA, sfRNA, antibody molecules (pg 20, last paragraph). Also envisaged are antagonists of ribonucleases antibody; may be a polyclonal antibody, monoclonal antibody, chimeric antibody (pg 23, last paragraph). Pharmaceutical compositions comprising RNA nuclease inhibitors may be administered orally, rectally, parenterally, topically (pg 46, 2nd paragraph). The composition is also administered by sustained release systems; semi-permeable polymer matrices in the form of shaped articles e.g., films or microcapsules. Sustained-release matrices include ethylene vinyl acetate (pg 46, last paragraph).
Above reference, Schneider, discloses that the size of the particle undergoing diffusion is one of the main governing factors determining the transport rate. The transport rate decreases with particle size (Section 3.3.3 Delivery of macromolecules/biologics). However, Schneider does not explicitly mention particles having a mean diameter of at least about 250 to about 1,000 nanometers.
Wang discloses implantable devices and particulate drug delivery systems that are being implemented and investigated (Abstract). Wang discloses an implant called vitrasert – a ganciclovir pellet coated in polyvinyl alcohol, a permeable polymer that allows drug diffusion, and ethylene vinyl acetate (EVA), an impermeable, a hydrophobic polymer that restricts release (section 2.1.1). Wang further discloses that drug delivery systems can include liposomes, microparticles, and nanoparticles. These are subdivided into micro- or nanospheres in which the drug is homogenously dispersed within a polymeric matrix and micro- or nanocapsules, in which the drug is encased ina polymeric membrane. Distinction is based on particulate size with microparticles generally accepted as 1 to 1000 microns in diameter and nanoparticles between 10 and 1,000 nanometers (Section 3.3). Wang teaches that size of carriers, such as liposomes, can be engineered based on application; those injected intravitreally are typically 100 nm to 400 nm in diameter (Section 3.3.1). Wang teaches that the particle sizes can be routinely engineered based on application.
Almarsson et al. teach nanoparticle compositions including an mRNA and a lipid component and methods of using the same (Abstract). A polymer may be included in and/or used to encapsulate mRNA, such as ethylene vinyl acetate polymer (EVA) ([0056]). Almarsson teaches that the wt/wt ratio of the lipid component to an mRNA in a nanoparticle may be from about 5:1 to about 50:1 ([0069]).
One of ordinary skill in the art would experiment with an implantable medical device comprising nucleic acid, carrier, and polymer matrix such as EVA with various wt. % of vinyl acetate. As discussed above, depending on the concentration of vinyl acetate, the melting temperature of the EVA polymer can be manipulated. Furthermore, the use of EVA polymer as a drug delivery device is well-established and many commercial products are available on the market (see Schneider’s et al. Tables 1 and 2). Bilban et al. also teach that ribonucleic acid degradation inhibitors are used with polymers of ethyl vinyl acetate within a pharmaceutical space. Wang teaches the importance of particle sizes. Almarsson et al. teach that mRNA and lipids are combined with polymers such as EVA for delivery of such composition into subjects in need.
Furthermore, one of ordinary skill in the art would experiment with various lipid carriers to mix with the polymer matrix such as EVA within an implantable medical device composition. One of the determinants is the similar ranges of melting temperature of the lipid carrier to the polymer matrix, especially for a method such as hot melt extrusion method. Alshetaili discloses that there are different processing variables that can be adjusted, including extrusion temperature (pg 1). Alshetaili discloses that hot melt extrusion (HME) depends on the temperature energy to melt the materials in order to produce a solid dispersion system. Choosing the optimum processing temperature range depends on the melting point and desirable formulation form (pg 4, last paragraph). The formulation of solid dispersion did not depend only on the melting temperature of CBZ (carbamazepine; active ingredient of study), but the overall melting temperature of the mixture of CBZ and Soluplus (carrier polymer of study) (pg 7, last paragraph). Similarly, one of ordinary skill in the art familiar with the hot melt extrusion method for creating a drug delivery system would routinely experiment with various melting temperatures of mixtures to optimize the process.
Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have combined an implantable medical device comprising carrier and encapsulated nucleic acid within EVA copolymer with specific melting temperature profile to deliver nucleic acid over a prolonged period of time. This is combining prior art elements according to known methods to yield predictable results such as an improved implantable medical device comprising nucleic acid with specific ratio of the melting temperature of polymer to carrier.
Regarding claim 2, Schneider et al. teach that the drug release could be readily customized via the blend ratio of the polymers (page 289, 1st paragraph). Furthermore, one of ordinary skill in the art would experiment with various weight ratios.
Regarding claim 3, melting temperature of ethylene vinyl acetate copolymer is discussed above.
Regarding claims 4-5, Slager et al. teach the carrier agents can include those compounds that can be complexed with nucleic acids in order to preserve the activity of the nucleic acids during manufacturing and delivery process. The carrier can include cationic lipids. Exemplary helper lipids can include phosphocholine, phosphoethanolamine. Other exemplary lipids can include lipioids, and PEGylated forms of lipids (col 4, lines 12-40). As with EVA melting points, one of ordinary skill in the art would experiment with different lipids with different melting points to optimize the implantable medical device. And it would have been obvious to do so in this instant application.
Regarding claim 6, Schneider et al. teach many EVA polymer pharmaceutical products as discussed above. Furthermore, one of ordinary skill in the art would experiment with EVA polymer as the only content of the polymer matrix.
Regarding claim 7, in some embodiments, Slager et al. teach mixing nucleic acid delivery particles, a first polymer, and a solvent/plasticizer to form a coating solution (col 1, lines 62-65).
Regarding claims 8-9, poly(ethylene-co-vinyl acetate) is discussed above. Furthermore, Schneider et al. teach that a number of active ingredients have ben studied in conjunction with EVA for implantable dosage forms (page 288, Implantable dosage form section).
Regarding claim 10, Slager et al. teach suitable polymers include poly(ethylene-co-vinyl acetate) having vinyl acetate concentrations of between about 10% and about 50% (col 19, lines 34-36).
Regarding claim 11, one of ordinary skill in the art would experiment with different melt flow index of polymers. Furthermore, the melt flow index value as claimed is within the normal physical melt flow ranges as shown in MatWeb (See NPL attached).
Regarding claim 12, Slager et al. teach the nucleic acids can be ribonucleic acids, deoxyribonucleic acids (col 4, lines 1-10).
Regarding claim 13, Almarsson et al. teach nanoparticle compositions including an mRNA and a lipid component and methods of using the same (Abstract). A polymer may be included in and/or used to encapsulate mRNA, such as ethylene vinyl acetate polymer (EVA) ([0056]).
Regarding claims 14, one of ordinary skill in the art would recognize that mRNA could comprise reading frames that would encode at least one antigenic polypeptide depending on what reading frames are incorporated. And it would have been obvious to do so in this instant case.
Regarding claims 20 and 22, specific lipid components are discussed above.
Regarding claim 23, helper lipid, structural lipids, PEG lipids are discussed above.
Regarding claim 24, Slager et al. teach that helper lipids can include cholesterol, and other phosphocholine and phosphoethanolamine compounds (col 4, lines 32-40).
Regarding claim 25, phospholipid and fatty acids are discussed above.
Regarding claim 26, Slager et al. teach lipids to include DC-cholesterol and other sterol compounds (col 4, line 25).
Regarding claim 28, Slager et al. teach spherical implant when viewed in cross-section (col 3, lines 9-10).
Regarding claims 29-31, Slager et al. teach that the delivery device can take on many different forms including a filament, cylinder, irregular shape or the like (col 3, lines 50-53). Furthermore, one of ordinary skill in the art would, through routine experimentation, experiment with different shapes and diameters of an implantable device.
Regarding claims 33, one of ordinary would experiment with different excipients such as RNA degradation inhibitor. An implantable device delivering RNA would benefit from RNA degradation inhibitor when it is being delivered to the body. And it would have been obvious to do so in this case. Bilban et al. also disclose anti-ribonuclease antibodies as discussed above.
Regarding claim 34, Almarsson et al. teach that additional agents can include chelating agents ([0063]).
Regarding claim 35, Almarsson et al. teach the nanoparticle composition to include permeability enhancing molecules ([0022]).
Regarding claim 36, Slager et al. teach natural or naturally-based polymers can include polysaccharides and modified polysaccharides such as starch, cellulose, chitin, chitosan, and copolymers thereof (col 9, lines 43-46).
Regarding claim 37, Slager et al. teach that the polymers can have hydrophilic polymers such as PEG block (col 6, lines 8-10).
Regarding claim 38, hydrophilic polymers are discussed above.
Regarding claim 39, Slager et al. teach the medical device comprises a first polymeric matrix, plurality of nucleic acid particles. Each nucleic acid delivery particle can include a second polymeric matrix. The medical device is configured to release the nucleic acid complex when the medical device is implanted within a subject (col 28, lines 16-40).
Regarding claim 40, Slager et al. teach formation of microparticles with various polymer blends (Table 1). Furthermore, one of ordinary skill in the art would experiment with different weight % ratios of particles to polymers for an implantable medical device. And it would have been obvious to do so in this instant case.
Regarding claim 41, Slager et al. teach that the drug delivery device can cover the drug release layer as shown in Figure. 2.
Regarding claim 42, Slager et al. teach that the particles are disposed within a matrix, forming an active agent delivery device (col 3, lines 15-22, also see Fig. 2).
Regarding claims 43-45, hydrophobic polymer such as ethylene vinyl acetate is discussed above.
Regarding claim 46, hydrophilic compounds are discussed above.
Regarding claim 47, Slager et al. teach the polymer blends through an extruder or mixer (col 24, lines 16-20). Furthermore, Schneider et al. teach that EVA is most commonly processed by hot-melt extrusion (page 286, 1st paragraph).
Regarding claim 48, hot-melt extrusion methods can comprise performing at various temperatures and one of ordinary skill in the art would experiment with different temperature ranges. And it would have been obvious to do so in this instant case.
Regarding claim 49, Schneider et al. teach that an implantable device is extruded using a small single screw extruder (page 288, left column, Subcutaneous implants section). Furthermore, one of ordinary skill in the art would experiment with different screw sizes to perform hot-melt extrusion. And it would have been obvious to do so in this instant case.
Regarding claim 51, Schneider discloses release of biological molecules from EVA matrices (Fig. 6). The amount of cyclosporin released in various % wt EVA matrices are shown in Figure 6B. Depending on the % wt of EVA matrix, the release rate can be controlled.
Regarding claim 52, Almarsson discloses that the invention features a method for the specific delivery of an mRNA to a target tissue; method includes administering to a subject a nanoparticle composition, said composition including a lipid component ([0012]).
Response to Arguments
Applicant’s arguments filed 08/25/2025 have been fully considered but they are not persuasive.
On pages 8-10 of remarks, Applicant argues that Slager discloses a different implantable composition; 1) Slager does not disclose particles that are solid lipid particles that only contain a lipid carrier component that encapsulates a nucleic acid (rather Slager discloses particles that contain a cationic compound for forming a complex as well as particle material 102 that may be a very wide range of materials); 2) Slager does not disclose particles wherein the ratio of the melting temperature of the EVA copolymer to the melting temperature of the lipid carrier is 2 degrees Celsius or less.
Claim 1 does not exclude other materials aside from solid lipid particles. Additionally, Almarsson teaches that lipid-containing nanoparticle compositions have proven effective as transport vehicles into cells and/or intracellular compartments for a variety of RNAs. These compositions generally include one or more cationic and/or ionizable lipids, phospholipids ([0003]). One of ordinary skill in the art would immediately envisage that RNAs can be delivered via a lipid carrier.
As evidenced by Alshetaili above, one of ordinary skill in the art would routinely experiment with various melting temperatures of mixtures for producing pharmaceutical formulations via a hot melt extrusion (HME) method. HME technique is widely used to produce pharmaceutical formulations including sustained-release formulations (pg 1, 1st paragraph).
Claim 1 broadly includes any and all solid lipid particles that include a lipid carrier encapsulating a nucleic acid, which is taught by Slager and Almarsson. The examiner cannot determine what separate the invention from prior arts. Is it due to an unexpected parameter? A specific blend of mixtures containing EVA, a specific lipid carrier, and nucleic acid? Does it work with any and all lipid carriers with a melting temperature proximal to EVA’s melting temperature? Is it the specific molar ratio of the carrier component to the nucleic acid? The examiner cannot determine such unexpected and/or critical difference from prior arts.
Conclusion
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/JOHN SEUNGJAI KWON/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615