DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after September 26, 2023, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Receipt is acknowledged of Applicants’ claimed invention filed on 09/26/2023 in the matter of Application N° 18/474,292. Said documents are entered on the record. The Examiner further acknowledges the following:
Thus, claims 1-20 represent all claims currently under consideration.
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.
Claim 18 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 18 recites “preferably”, which is indefinite because it is unclear whether the preferred temperature is an actual claim limitation or not.
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 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Slager et al. (US8883208B2), in view of Schneider et al. (Applications of ethylene vinyl acetate in drug delivery systems, Journal of Controlled Release, 2017), further evidenced by MatWeb (overview of materials for EVA, Film Grade, Website established 2011), and Wang et al. (US20210285002A1).
Slager et al. disclose an implantable medical device for the controlled release of nucleic acid therapeutics. Specifically, Slager et al. teach an implantable medical device comprising a polymeric matrix and a nucleic acid complex disposed within the polymeric matrix (Abstract). The nucleic acid complex includes a nucleic acid and a carrier agent, wherein the nucleic acid may be any of a variety of nucleic acids capable of providing a therapeutic effect (col. 4, lines 1-5). Slager et al. further disclose suitable polymeric matrices comprising poly(ethylene-co-vinyl acetate) (EVA) copolymers having vinyl acetate concentrations between about 19% and about 50% (col. 19, lines 34-36).
Slager et al. therefore teach an implantable medical device comprising a core polymer matrix containing a nucleic acid therapeutic. Slager et al. additionally demonstrate the controlled release of nucleic acid therapeutics from polymeric delivery particles over time, as illustrated by the release profiles of siRNA/peptide complexes (See Fig. 6).
Slager et al. do not expressly disclose that the nucleic acid is an antisense oligonucleotide comprising one or more nucleosides attached via internucleoside linkages, wherein at least 10% of the internucleoside linkages are chemically modified.
Wang et al. teach antisense oligonucleotides comprising regions of complementarity to a target transcript for therapeutic applications (See paragraph 0003). Antisense oligonucleotides are known nucleic acid therapeutic agents comprising nucleosides connected through internucleoside linkages, including chemically modified internucleoside linkages commonly employed to improve stability, nuclease resistance, and pharmacological performance.
It would have been obvious to one of ordinary skill in the art at the time the invention was made to substitute the antisense oligonucleotides of Wang et al. for the broadly disclosed nucleic acids of Slager et al. because Slager et al. expressly contemplate the use of various therapeutic nucleic acids within the implantable polymeric matrix. Such substitution would merely represent the use of one known nucleic acid therapeutic in place of another to obtain the predictable benefit of localized and sustained nucleic acid delivery.
Schneider et al. teach that ethylene vinyl acetate copolymers are widely used in controlled drug delivery systems and that their crystallinity, polarity, stiffness, and melting behavior are governed primarily by vinyl acetate content. Schneider et al. further teach that EVA having low vinyl acetate content exhibits melting temperatures of about 110-120°C, whereas increasing vinyl acetate content decreases the melting temperature, resulting in softer and more amorphous polymers with melting temperature, resulting in softer and more amorphous polymers with melting temperatures of about 45-55°C at approximately 40 wt.% vinyl acetate (See Introduction; Table 1). These teachings evidence that EVA properties, and consequently drug release characteristics, may be adjusted through routine selection of EVA composition.
Regarding the limitation requiring that from about 5% to about 60% of the antisense oligonucleotide be released after about seven days, Slager et al. teach controlled release of nucleic acid therapeutics from polymeric matrices over time (See Fig. 6.). The precise amount released after a given period of time is recognized as a result-effective variable dependent upon factors such as polymer composition, loading level, molecular weight, diffusivity, and formulation parameters. One of ordinary skill in the art would have been motivated to optimize these known variables through routine experimentation to achieve a desired release profile, including release amounts falling within the claimed range. Discovering an optimum or workable value of a result-effective variable is ordinarily within the skill of the art.
Accordingly, it would have been obvious to one of ordinary skill in the art to formulate the antisense oligonucleotide of Wang et al. within the EVA polymer matrix of Slager et al., as further informed by the EVA property teachings of Schneider et al., and to optimize the release characteristics through routine experimentation, thereby arriving at the claimed implantable medical device.
Regarding claim 2, Slager et al. disclose an implantable medical device comprising a nucleic acid therapeutic dispersed within a polymeric matrix, wherein the polymeric matrix may comprise poly (ethylene -co-vinyl acetate) copolymer (See col 19 lines 34-36). Slager et al. further teach that the amount of nucleic acid incorporated into the polymeric matrix may be varied to achieve desired therapeutic loading and release characteristics.
Slager et al. do not expressly disclose a weight ratio of polymer matrix to antisense oligonucleotide of from about 1 to about 10.
However, the relative amounts of polymer and active agent in a controlled-release implant are recognized as variables affecting drug loading, release rate, diffusion characteristics, and therapeutic performance. Slager et al. teach controlled release of nucleic acid therapeutics from polymeric matrices and demonstrate that release characteristics depend upon formulation parameters. Therefore, one of ordinary skill in the art would have been motivated to optimize the relative amounts of polymer matrix and nucleic acid therapeutic through routine experimentation to obtain a desired loading capacity and release profile.
The claimed weight ratio of polymer matrix to antisense oligonucleotide represents merely an optimization of a result-effective variable. Discovering an optimum or workable value of a result-effective variable ordinarily falls within the level of ordinary skill in the art. In the absence of evidence demonstrating criticality or unexpected results associated with the claimed range, selecting a polymer-to-ASO weight ratio of from about 1 to about 10 would have been obvious to one of ordinary skill in the art at the time of the invention.
Regarding claim 3, Schneider et al. teach that ethylene vinyl acetate (EVA) is a well-known polymer used in controlled drug delivery systems (See Table 1; and Introduction). Schneider et al. further disclose that the physical properties of EVA, including crystallinity melting temperature, stiffness, and polarity are primarily dependent upon the vinyl acetate (VA) content of the copolymer. Specifically, EVA having little or no vinyl acetate exhibits melting temperature of approximately 110°C to 120°C, while increasing the vinyl acetate concentration lowers the melting temperature. Schneider et al. disclose that EVA containing approximately 40wt.% vinyl acetate exhibits a broad melting temperature range of about 45°C to 55°C and possesses a more amorphous and flexible character (See page 285, properties of EVA).
Accordingly, Schneider et al. teach that the melting temperature of EVA can be predictably controlled by adjusting the vinyl acetate content. Because Slager et al. expressly disclose EVA copolymers containing between about 19% and about 50% vinyl acetate, one of ordinary skill in the art would have understood that selecting an EVA copolymer having a melting temperature within the claimed range of about 20°C to about 100°C would have been a matter of routine optimization of a known property of the polymer. The claimed melting temperature therefore represents the predictable result of selecting an EVA copolymer with an appropriate vinyl acetate concentration and would have been obvious to one of ordinary skill in the art.
Regarding claim 4, Slager et al. disclose an implantable medical device comprising a nucleic acid therapeutic dispersed within a polymeric matrix comprising ethylene vinyl acetate (EVA). However, Slager et al. do not expressly disclose that the EVA polymer possesses a melt flow index of from about 0.2 to about 100 grams per 10 minutes as determined in accordance with ASTM D1238-20 at 190°C under a load of 2.16 kilograms. It is well known in the art that the melt flow index is a physical property of thermoplastic polymers that reflects the flow characteristics and processability of the material. One of ordinary skill in the art would have recognized that the melt flow index of EVA may be selected based on the desired manufacturing and performance characteristics of the implantable medical device, including polymer processing, drug incorporation, and release behavior.
Furthermore, the non-patent literature (MatWeb) demonstrates that EVA materials are commercially available with melt flow index values spanning the claimed range. Accordingly, the claimed melt flow index represents a known and conventional property of EVA polymers. Selecting an EVA polymer having a melt flow index of about 0.2 to about 100 g/10 min would have been an obvious matter of routine design choice and optimization of a result-effective variable, absent evidence of criticality or unexpected results associated with the claimed range.
Therefore, it would have been obvious to one of ordinary skill in the art at the time of the invention to utilize an EVA polymer having a melt flow index within the claimed range in the implantable medical device of Slager et al.
Regarding claim 5, Slager et al. disclose that suitable polymeric matrices for the implantable medical device include poly (ethylene-co-vinyl acetate) copolymers having vinyl acetate concentrations between about 19% and about 50% (See col. 19, lines 34-36).
The claimed vinyl acetate content of from about 10 wt% to about 60 wt% encompasses the range expressly taught by Slager et al. because the range disclosed by Slager et al. substantially overlaps, and indeed falls entirely within, the claimed range, a prima facie case of obviousness is established. It is well settled that discovering an optimum value of a result-effective variable within a known range is ordinarily within the skill of the art.
Furthermore, Schneider et al. teach that the physical properties of ethylene vinyl acetate copolymers, including crystallinity, melting temperature, stiffness, and polarity, are influenced by the vinyl acetate content. Therefore, one of ordinary skill in the art would have been motivated to select a vinyl acetate concentration within the known range to obtain desired polymer properties and release characteristics for the implantable medical device. Accordingly, selecting a vinyl acetate content from about 10 wt% to about 60 wt% would have been obvious to one of ordinary skill in the art at the time of the invention.
Regarding claim 6, Wang et al. disclose antisense oligonucleotides that are complementary to a frataxin (FXN) transcript and teach that the antisense oligonucleotides may have lengths ranging from about 8 nucleotides to about 80 nucleotides. The claimed antisense oligonucleotide length of from about 8 nucleoside subunits to about 50 nucleoside subunits overlap substantially with the range disclosed by Wang et al. it is well established that where the claimed range overlaps or lies within a range disclosed by the prior art (See claim 22). A person of ordinary skill in the art would have reasonably expected antisense oligonucleotides having lengths within the claimed range to possess the same intended antisense activity as those taught by Wang et al.
Furthermore, the selection of a particular oligonucleotide length within the disclosed range would have been a matter of routine optimization based on factors such as target binding affinity, specificity, stability, and therapeutic efficacy. Absent evidence of criticality or unexpected results associated with the claimed range, selecting an antisense oligonucleotide having a length of about 8 to about 50 nucleoside subunits would have been obvious to one of ordinary skill in the art.
Accordingly, it would have been obvious to utilize an antisense oligonucleotide having the claimed length in the implantable medical device of Slager et al. as modified by Wang et al.
Regarding claim 7, Wang et al. disclose antisense oligonucleotides and further teach that the terms “polynucleotide” and “nucleic acid molecule” refer to polymers of nucleotides joined together by phosphorothioate linkages between the 5’ and 3’ carbon atoms. Wang et al. additionally teach that the phosphate group of a nucleotide may be chemically modified, for example, by substituting one or more oxygen atoms with sulfur to form phosphorothioate linkages (See paragraphs 0135 and 0141).
The claimed limitation requires that from about 10% to about 90% of the internucleoside linkages in the backbone of the antisense oligonucleotide comprise chemically modified internucleoside linkages, including phosphorothioate linkages, to improve the properties of antisense oligonucleotides. The extent of backbone modification constitutes a recognized result-effective variable that influences nuclease resistance, stability, pharmacokinetics and biological activity. One of ordinary skill in the art would have understood that the percentage of modified internucleoside linkages may be adjusted depending upon the desired balance of stability and biological performance. Accordingly, optimizing the proportion of chemically modified internucleoside linkages through routine experimentation, including selecting a proportion within the claimed range of about 10% to about 90%, would have been obvious absent evidence of criticality or unexpected results associated with the claimed range.
It would have been obvious to utilize an antisense oligonucleotide having from about 10% to about 90% chemically modified internucleoside linkages in the implantable medical device of Slager et al. as modified by Wang et al.
Regarding claim 8, Wang et al. expressly teach chemically modified phosphate backbones in antisense oligonucleotides, including phosphorothioate linkages formed by substituting sulfur for one or more oxygen atoms of the phosphate group ((See paragraphs 0135 and 0141). Because phosphorothioate linkages are specifically disclosed as modified internucleoside linkages, the claimed limitation is directly taught by Wang et al. and would have been obvious for incorporation into the implantable nucleic acid delivery device of slager et al. to improve oligonucleotide stability and durability.
Regarding claim 9, Wang et al. disclose in certain embodiments, at least one nucleotide of the antisense oligonucleotide comprises a phosphorodiamidate morpholino (PMO) nucleotide. In certain embodiments, every nucleotide of the antisense oligonucleotide comprises a phosphorodiamidate morpholino nucleotide (See paragraph 0023).
Regarding claim 10, Wang et al. disclose antisense oligonucleotides comprising chemically modified nucleotide sequences. Specifically, Wang et al. teach antisense oligonucleotides having sequence modification patterns in which phosphorothioate internucleoside linkages are present throughout the oligonucleotide backbone, and wherein certain nucleotides comprise 2’-O-(2-methoxyethyl) modifications while other nucleotides comprise 2’-deoxymodifications (See paragraph 0055).
Wang et al. therefore teach the well-known gapmer configuration in which a central region of 2’-deoxyribonucleosides is flanked by wing regions containing 2’-o-(2-methoxyethyl) modified ribonucleotides. Such arrangements are utilized to provide RNase H activity while improving nuclease resistance, binding affinity, and pharmacokinetic properties (See paragraph 0055).
The claimed limitation recites an antisense oligonucleotide comprising a gap region having about 8 to about 10 contiguous 2’-deoxyribonucleosides and first and second wing regions flanking the gap region, wherein each wing region independently comprises 1 to 8 2’-O-(2-methoxyethyl) ribonucleotides. Wang et al. teach both the recited nucleotide modifications and the use of modified and unmodified nucleotide regions within the same antisense oligonucleotide. The selection of the particular number of nucleotides within the gap region and wing regions would have been an obvious matter of routine optimization based upon desired antisense activity, RNase H recruitment, target affinity, stability, and pharmacological performance.
It would have been obvious to one of ordinary skill in the art to utilize a gapmer antisense oligonucleotide having a central 2’-deoxyribonucleoside region and flanking 2’-O-(2-methoxyethyl) ribonucleotide wing regions, including the claimed nucleotide lengths, in the implantable medical device of Slager et al. as modified by Wang et al.
Regarding claim 11, Wang et al. disclose antisense oligonucleotides comprising specific sequence modification patterns, wherein “S” represents a phosphorothioate internucleoside linkage. Wang et al. further teach antisense oligonucleotides containing 2’-O-(2-methoxyethyl) modified nucleotides and 2’-deoxy modified nucleotides in combination with phosphorothioate internucleoside linkages (See claim 55, and paragraph 0055).
The claimed limitation requires that the internucleoside linkages in the first wing region and the second wing region comprise phosphorothioate linkages. Wang et al. expressly teach the use of phosphorothioate internucleoside linkages in antisense oligonucleotides and identify such linkages as a preferred backbone modification for improving nuclease resistance, stability, and therapeutic performance.
It would have been obvious to one of ordinary skill in the art to employ phosphorothioate internucleoside linkages in the wing regions of the antisense oligonucleotide incorporated into the implantable medical device of Slager et al., as modified by wang et al., in order to obtain the known benefits associated with phosphorothioate backbone modifications.
Regarding claim 12, Wang et al. disclose antisense oligonucleotides comprising nucleic acid sequences having at least 90% sequence identity to the disclosed SEQ ID Nos (See claim 51). Wang et al. further teach antisense oligonucleotides containing phosphorothioate internucleoside linkages, wherein “S” represents a phosphorothioate linkage. The use of phosphorothioate linkages is disclosed as a backbone modification that improves oligonucleotide stability and resistance to nuclease degradation.
The claimed limitation requires that at least 75% of the internucleoside linkages in the gap region comprise phosphorothioate linkages. Wang et al. teach the use of phosphorothioate backbone modifications in antisense oligonucleotides and would have suggested employing such modifications throughout a substantial portion of the oligonucleotide, including the gap region. The proportion of phosphorothioate linkages represents a recognized result-effective variable affecting stability, pharmacokinetics, and antisense activity.
One of ordinary skill in the art would have been motivated to optimize the degree of phosphorothioate modification within the gap region, including employing phosphorothioate linkages in at least 75% of the internucleoside linkages, as a matter of routine experimentation to obtain the known benefits associated with phosphorothioate modified antisense oligonucleotides.
Regarding claim 13, Wang et al. disclose antisense oligonucleotides comprising gapmer motifs configured to direct RNase H-mediated cleavage of a frataxin (FXN) transcript. Wang et al. teach that the gapmer motif may be described by the formula “ABC”, wherein “A” represents the length of the 5’ wing region, “B” represents the length of the gap region, and “C” represents the length of the 3’ wing region. Wang et al. further disclose that the gap region may comprise from about 6 to about 18 DNA nucleotides and/or DNA-like nucleotides (See paragraphs 0163 and 0168). Importantly, Wang et al. expressly identify numerous gapmer formats suitable for use in the disclosed antisense oligonucleotides, including 1-10-1, 1-11-1, 5-6-5, and 5-10-5 gapmers (See paragraph 0168). Thus, Wang et al. specifically teach an antisense oligonucleotide comprising a 5-10-5 gapmer motif.
It would have been obvious to one of ordinary skill in the art to utilize the expressly disclosed 5-10-5 gapmer antisense oligonucleotide of Wang et al. in the implantable medical device of Slager et al., since Wang et al. teach that such gapmer structures are suitable for RNase H-mediated target RNA cleavage and antisense therapeutic activity.
Regarding claim 14, Slager et al. disclose implantable medical devices comprising a nucleic acid therapeutic dispersed within a polymeric matrix, wherein the amount of nucleic acid and polymer matrix may be varied to achieve desired therapeutic loading and release characteristics. Slager et al. further teach controlled release of nucleic acid therapeutics from polymeric matrices over time.
Slager et al. do not expressly disclose that the antisense oligonucleotide constitutes from about 50 wt% to about 70 wt% of the core and that the polymer matrix constitutes from about 50 wt% to about 30 wt% of the core.
However, the relative proportions of active agent and polymer matrix are recognized formulation parameters that directly affect drug loading, release kinetics, diffusivity, mechanical properties, and therapeutic performance. One of ordinary skill in the art would have understood that the amounts of antisense oligonucleotide and polymer matrix may be adjusted to achieve a desired release profile and therapeutic effect. The claimed weight percentages represent optimization of known result-effective variables. Routine experimentation directed to balancing drug loading and controlled release would have led one of ordinary skill in the art to select amounts of antisense oligonucleotide and polymer matrix within the claimed ranges. In the absence of evidence demonstrating criticality or unexpected results associated with the claimed weight percentages, the recited ranges would have been obvious design choices.
It would have been obvious to utilize a core comprising about 50 wt% to about 70 wt% antisense oligonucleotide and about 50 wt% to about 30 wt% polymer matrix in the implantable medical device of Slager et al. as modified by Wang et al.
Regarding claim 15, Slager et al. teach a medical device having a controlled-release coating comprising a polymeric matrix disposed on the surface of the device and containing nucleic acid delivery particle (See claim 1). Slager et al. teach that the polymers can have hydrophilic polymers such as PEG block. (See col 6, lines 8-10). Wang et al. further teach the use of hydrophobic components in antisense oligonucleotide delivery systems to improve membrane interactions (See paragraph 0264). Because hydrophobic and hydrophilic materials were routinely employed in controlled-release coatings to modulate permeability and release characteristics, one of ordinary skill in the art would have found it obvious to provide the polymeric coating of Slager et al. with hydrophobic and hydrophilic constituents, thereby arriving at the claimed membrane layer.
Regarding claim 16, Slager et al. disclose implantable medical devices and controlled-release systems for delivering nucleic acid therapeutics from polymeric matrices. Specifically, Slager et al. teach the release of nucleic acid-containing particles over time and demonstrate release kinetics for nucleic acid therapeutics from polymeric delivery systems (See e.g., Fig. 6). Slager et al. do not expressly disclose a cumulative antisense oligonucleotide release ratio of from about 60% to about 80% after a period of about 10 days.
However, the cumulative amount of therapeutic agent released from a controlled-release device over a given period of time is a recognized result-effective variable influenced by factors such as polymer composition, polymer loading, active-agent loading, molecular weight, diffusivity, coating characteristics, and device geometry. One of ordinary skill in the art would have understood that these formulation and device parameters could be adjusted to obtain a desired release profile.
Because Slager et al. teach controlled release of nucleic acid therapeutics from polymeric matrices, it would have been obvious to optimize the release characteristics of the device through routine experimentation to achieve a cumulative release ratio within the claimed range of about 60% to about 80% after about 10 days. In the absence of evidence demonstrating criticality or unexpected results associated with the claimed release range, the recited release profile represents the predictable result of optimizing known release parameters.
It would have been obvious to one of ordinary skill in the art to arrive at an implantable medical device exhibiting a cumulative antisense oligonucleotide release ratio of about 60% to about 80% after about 10 days.
Regarding claim 17, Slager et al. disclose implantable medical devices comprising nucleic acid therapeutics dispersed within polymeric matrices, including poly (ethylene-co-vinyl acetate) copolymers. Slager et al. further teach controlled-release devices comprising nucleic acid-containing polymeric matrices suitable for implantation.
Schneider et al. teach that ethylene vinyl acetate copolymers are widely used in drug delivery systems and that the physical properties of EVA are dependent upon the vinyl acetate content. Furthermore, commercially available EVA materials are known to possess a wide range of melt flow indices, including values falling within the claimed range of about 1 to about 400 g/10min, as evidenced by the non-patent literature (MatWeb).
It is well known in the polymer processing art that thermoplastic polymers such as EVA are manufactured into implantable and controlled release devices by melt blending the polymer and active ingredient, mixing the components within an extruder barrel, extruding the resulting mixture to form a desired shape, cooling the extrudate, and cutting the cooled material into individual devices. Such processing steps represent conventional extrusion operations routinely employed to produce polymer-based drug delivery devices.
It would have been obvious to one of ordinary skill in the art to manufacture the implantable nucleic acid delivery device of Slager et al. by melt blending an EVA polymer matrix and antisense oligonucleotide in an extruder, mixing the components at suitable processing temperatures, extruding the resulting blend to form a core, cooling the core, and cutting the core into individual implantable devices. The selection of processing temperatures and EVA grades having melt flow indices within the claimed range would have been a matter of routine optimization of known manufacturing parameters.
Regarding claim 18, Schneider et al. teach that the thermal properties of ethylene vinyl acetate (EVA), including its melting temperature and processability, are dependent upon the vinyl acetate content of the copolymer. Specifically, Schneider et al. disclose that EVA having increased vinyl acetate content exhibits melting temperatures of approximately 45°C to 55°C, resulting in a softer and more amorphous polymer suitable for processing in drug delivery applications.
Slager et al. disclose implantable medical devices comprising EVA-containing polymer matrices for delivery of nucleic acid therapeutics. As discussed above, it would have been obvious to manufacture such devices using conventional melt-blending and extrusion techniques.
The claimed first temperature of from about 30°C to about 60°C represents a process variable associated with the handling, softening, and processing of the EVA polymer.
One of ordinary skill in the art would have selected an appropriate processing temperature based on the known thermal characteristics of the EVA material being utilized. In view of Schneider et al.’s teaching that EVA compositions may exhibit melting temperatures within or near the claimed range, selecting a first temperature of about 30°C to about 60°C, including about 50°C, would have constituted routine optimization of a known process parameter.
Accordingly, it would have been obvious to employ a first processing temperature within the claimed range when melt-blending and extruding the EVA-containing polymer matrix and antisense oligonucleotide to form the implantable medical device.
Regarding claim 19, Schneider et al. teach that the physical and thermal properties of ethylene vinyl acetate, including melting behavior and processability, are dependent upon the vinyl acetate content of the copolymer. Schneider et al. further disclose EVA materials exhibiting melting temperatures in the range of approximately 45°C to 55°C at elevated vinyl acetate concentrations.
As discussed above, it would have been obvious to manufacture the implantable medical device of Slager et al. using conventional melt-blending and extrusion techniques. During such manufacturing processes, processing temperatures are routinely selected and adjusted to facilitate mixing, blending, and extrusion of the polymer and therapeutic agent while maintaining suitable material properties.
The claimed second temperature of from about 60° to about 70°C, including about 65°C, represents a process variable associated with the extrusion and mixing operation. One of ordinary skill in the art would have selected a suitable processing temperature based upon the known thermal properties, melt characteristics, viscosity, and flow behavior of the EVA polymer. Optimizing the mixing temperature to achieve efficient blending and extrusion would have been a matter of routine experimentation.
Accordingly, it would have been obvious to employ a second temperature within the claimed range of about 60°C to about 70°C, including about 65°C, when mixing the polymer matrix and antisense oligonucleotide in the extrusion process. The claimed temperature therefore constitutes a routine optimization of a known process parameter.
Regarding claim 20, Schneider et al. teach manufacturing a rod-shaped implantable device by hot-melt extrusion using a small single-screw extruder (See page 288, left column, subcutaneous implants section). Thus, Schneider et al. disclose the use of conventional extrusion equipment for producing implantable polymer-based drug delivery devices.
Schneider et al. do not expressly disclose that the extruder barrel includes a rotatable screw having a length-to-diameter ratio of from about 10 to about 50.
However, the screw length to diameter (L/D) ratio is a well-known design parameter in extrusion processing that affects residence time, mixing efficiency, melting, homogenization, and throughput of the polymer composition. one of ordinary skill in the art would have recognized that the selection of an appropriate screw L/D ratio depends upon the polymer formulation and the desired processing characteristics. Accordingly, it would have been obvious to select a screw having a length-to-diameter ratio within the claimed range through routine optimization and experimentation to achieve efficient hot-melt extrusion of the ethylene vinyl acetate polymer matrix and antisense oligonucleotide. Therefore, employing an extruder having a screw length-to-diameter ratio of from about 10 to about 50 would have been an obvious matter of routine process optimization and design choice.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference
claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321 (d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AlA. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection |.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 5, and 14-20, are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 9, 11, 22, 24-25, 27, 29-30, and 31-34, of copending Application No. 17/705,441 and 17/705,444 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims disclose an implantable medical device comprising an antisense oligonucleotide (ASO) dispersed within a core polymer matrix comprising an ethylene vinyl acetate complex.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not been patented.
Conclusion
No claim is allowed.
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/KIMBERLY BARBER/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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