DEVICE FOR INTRAOCULAR RELEASE OF A MEDICAMENT

DETAILED ACTION Notice of Pre-AIA or AIA Status The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Claim 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. Claims 1, 3-4, 6-8, 10-12, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Imran (previously cited) in view of Aghion et al. (previously cited) and Pryce er al. (previously cited) as evidence by Wong et al. (previously cited). Imran teaches a muti-stage degradable drug delivery platform for sequential release of contained drugs (see abstract). The walls of the device sequentially dissolve/degrade in vivo (see paragraph 18; instant claim 1). They teach the device as needle shaped which implies a cylindrical shape (see paragraph 16). An embodiment providing two delivery stages is arranged as an outer hollow degradable shell within which is inscribed an inner hollow degradable shell as shown in figure 1A below (see paragraph 17 and figure 1A): PNG media_image1.png 300 622 media_image1.png Greyscale Here components 102 and 108 are the outer and inner hollow shells/solids, respectively, while components 103 and 109 are the instant crown and core regions (see paragraph 17; instant claim 1). They detail that the degradable material is envisioned as magnesium or a magnesium alloy with aluminum, lithium, calcium, manganese and/or zinc such that the outer shell and inner shell materials are different (see paragraph 17; instant claims 1 and 4). A cavity outside the inner shell (component 103) that is defined by the outer shell (crown) contains drug as does a cavity inside the inner shell (component 109) (core volume) (see paragraph 17). Components 106 and 110 represent drug located in the hollow region of the outer (crown) and inner shell (core) which may be in the form of a liquid, gel, colloid, or solid (see paragraphs 9 and 17; instant claim 1). Imran goes on to teach that the thickness of the inner wall component 108 is greater than that of outer wall 102 (increasing from outermost to innermost) so that the time for release of the inner drug component 110 is greater than that of the outer drug component 106 (see paragraph 18; instant claims 1 and 12). They additionally teach that such thicknesses can be selected to yield the desired duration of time between releases from each shell (see paragraphs 18-19; instant claims 1 and 15). Component 104 is a penetrating end (end cap) that may be the same or a different material as component 102 (see paragraph 16). An additional hollow region with a third quantity of drug inside the device is also envisioned to yield a third delivery period after degradation of its wall (see paragraph 21; instant claim 7). Imran further teaches the device for subcutaneous implantation, where its size can vary based on the size of the patient and they envision the wall thickness of the inner shell to range from 0.001 to 0.02 in (about 25-500 mm) (see paragraphs 18-19 and 28). They also envision loaded drugs in the device to include antibiotics (see paragraph 25). Imran does not explicitly teach the degradable shells in their device to have common openings (e.g., concentric bases/ends). Aghion et al. teach a magnesium alloy implant configured as a layered construct with two or more layers (inscribed hollow solids), where at least one is the magnesium alloy and they differ in magnesium composition (see abstract and paragraph 197 and 208; instant claims 1 and 15). They go on to teach a core where a sequence of layers are applied (see paragraph 199). Aghion et al. detail the inclusion of an active substance for sustained release that is envisioned as a variety of drugs which include anti-inflammatory agents, proteins (biological material), antibiotics, and DNA (biological material) (see paragraphs 212, 218 and 221; instant claim 3). Anti-inflammatory agents are also known to treat intraocular pathologies (see Wong et al. column 1 lines 14-23). A rod shape with a circular cross-section (cylinder) is exemplified and rods as well as more generic surgical implants are named as well (see paragraphs 216 and 269 and figures 1 and 8). The metal can be shaped in a variety of ways including melting and casting as well as extrusion, thereby generating degradable materials (see paragraphs 255-256 and 272). They further envision subcutaneous implantation (see paragraph 377). Pryce et al. teach layered drug delivery device forms with various configurations where one is composed of a core covered by a series of layers that are all cylindrical in shape and another that is a series of nested cylinders (see figures 3A and 5). The arrangement of layers and end caps provide radial release and an embodiment shown below from figure 5, provides components 610 and 612 as the degradation resistant end caps that close the common openings of the cylindrical core that is component 635 and the components 631-634 that are concentric hollow cylinders with concentric ends. Here, component 631 is the outermost hollow solid and the region between this feature and an inner wall is a crown volume. PNG media_image2.png 400 402 media_image2.png Greyscale The cylindrical shape is further taught to degrade radially, through the curved wall, and release drug as a result of this degradation due to its initially open ends being covered by caps which resist degradation (guarantee maintenance until degradation of the innermost solid) (see paragraphs 24, 72, and 153 and figure 2B and 5; instant claim 1). The innermost region followed by one layer or a succession of layers have a zero or non-zero concentration of drug (see paragraph 78). This radial release and the depicted configuration requires the end caps to seal every region produced by the concentric layers/regions 631-635 (see instant claim 1 and 15). Figure 3A, shown below, PNG media_image3.png 205 273 media_image3.png Greyscale provides a series of cylinders inscribed inside one another, where component 335 is the core and components 331-334 are concentric hollow cylinders that encapsulate each smaller sized cylinder (see paragraph 79). They additionally teach alternative shapes such as rectangular prisms (parallelepiped) and spheres (see paragraph 72). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to configure the drug containing implant of Imran with magnesium alloys of differing composition as the inner and outer shell because they suggest magnesium as the degradable material to compose the walls of the device and differing rates of degradation for the walls that contain each drug portion. Aghion et al. further support this choice for a magnesium based implant that provides concentric cylindrical layers that are composed of magnesium of different composition and therefore differing degradation properties. Similarly, it also would have been obvious to select a liquid for the drug portions in the inner and outer cylinders of Imran because they suggest to do so. This liquid in the outer shell, but outside of the inner shell would fill the void volume between the two shells and take on the shape of this void. In light of Pryce et al. and the alternative arrangements of implants composed of concentric cylinders that provide sequential release of drugs, it also would have been obvious to configure the device of Imran such that the bases of the cylindrical shells are concentric and closed by a magnesium alloy pointed endcap on one end and a magnesium alloy blunt endcap on the other like Pryce et al. figure 5 (see instant claims 1 and 15). This modification in configuration would have been obvious as the simple substitution of one known element/configuration for another in order to yield a predictable outcome and as the application of the same technique to a similar product in order to yield the same improvement. This configuration of the magnesium endcaps follows from the suggestion of Imran to make the pointed tip the same material as the outer shell. The result would be the instantly claimed hollow solids inscribed one into the other with a core volume and crown volume filled with liquid drug that constrains drug release to the radial surface of the implant. The implementation of a third concentric interior shell for a third stage of drug release would follow as suggested by Imran (see instant claims 7-8). Similarly, a parallelepiped shape as opposed to a cylinder shape also would have been obvious from the teachings of Pryce et al. who teach them as alternative geometries (see instant claim 10). The preparation of the device implicitly requires making the layered structure and loading the core and spaces between the walls with drug. Additionally it would have been obvious to select an anti-inflammatory agent for the drug of Imran in light of Aghion et al. as the simple substitution of one known element for another in order to yield a predictable outcome. The compounds of instant claim 6 are met by this selection because the claim adds further limitations for the anti-VEGF compounds of claim 3, but do not require that one of them be selected. The recitation “intraocular” is an intended use that does not distinguish the claimed device from the structure of the modified device of Imran et al. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. The device rendered obvious by Imran in view of Aghion et al. and Pryce et al. can have a size that could be employed for intraocular drug delivery and pathology treatment; thus the intended use requirements are met. Therefore claims 1, 3-4, 6-8, 10-12, and 15 are obvious over Imran in view of Aghion et al. and Pryce et al. as evidenced by Wong et al. Claim 1, 3-8, 10-12, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Imran in view of Aghion et al. and Pryce et al. as evidenced by Wong et al. as applied to claims 1, 3-4, 6-8, 10-12, and 15 above, and further in view of Mao et al. (previously cited). Imran in view of Aghion et al. and Pryce et al. as evidenced by Wong et al. render obvious the limitation of instant claims 1, 3-4, 6-8, 10-12, and 15. Various alloys of magnesium are envisioned by Imran; however, a magnesium alloy with the instantly claimed composition is not detailed. Mao et al. teach a magnesium alloy termed JDBM with a formula Mg-2.5Nd-.2Zn-0.4Zr for implant applications (see abstract; instant claim 5). The material offers superior control of degradation rates over other varieties of magnesium alloy as well as more uniform degradation (see figures 1-2). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ the magnesium alloy of Mao et al. as the magnesium material in the device of Imran in view of Aghion et al. and Pryce et al. as evidenced by Wong et al. This choice would have been obvious as the simple substitution of one known element for another in order to yield a predictable outcome and as the application of the same technique to a similar product in order to yield the same improvement. Therefore claims 1, 3-8, 10-12, and 15 are obvious over Imran in view of Aghion et al., Pryce et al., and Mao et al. as evidenced by Wong et al. Claims 1, 3-4, 6-8, 10-12, 15-16, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Imran in view of Aghion et al. and Pryce et al. as evidenced by Wong et al. as applied to claims 1, 3-4, 6-8, 10-12, and 15 above, and further in view of Reiff et al. (previously cited) and Varner et al. (previously cited). Imran in view of Aghion et al. and Pryce et al. as evidenced by Wong et al. render obvious the limitation of instant claims 1, 3-4, 6-8, 10-12, and 15. The device provides an increasing thickness of the wall moving from outermost to innermost, as detailed by Imran, thereby being configured for sequential (staged) dissolution/degradation and release of drug, as they also intend. Ocular applications are not explicitly detailed. Much like the implant rendered obvious by the modified teachings of Imran, Reiff et al. teach an elongate degradable drug releasing device for implantation to provide controlled release (see abstract, paragraph 50-53, and figures 1A, 3B, and 4A). They teach the tube device to have a cross section with various shapes such as a polygon, rectangle, and circle which releases its contents via degradation and diffusion (see paragraphs 215-216 figures 1A, 3B, and 4A). The device is envisioned with layers that release in series (see paragraphs 51-52). Reiff et al. go on to teach the utility of such devices as intraocular implants, where they are placed in the posterior chamber of the eye to release a desired drug or drug combination (see paragraph 31). The drugs of interest include anti-inflammatory agents and anti-agents that act against chemokines such as vascular endothelial growth factor (VEGF) (see paragraph 44; instant claims 3 and 18). Varner et al. teach the utility of magnesium as a material that provides structural support and acts as a physical carrier onto which drug is loaded in an ocular implant (see abstract and paragraphs 22 and 24). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ the modified device of Imran as an intraocular implant that releases a drug relevant to the eye. This choice would have been obvious in light of Varner et al. who teach that magnesium as a compositional material for ocular implants that is suitable and Reiff et al. who teach the utility of similarly structured and functioning devices in the eye. More specifically, selecting an anti-inflammatory agent (instant claim 3 and 6) or an anti-VEGF compound (instant claim 18) for the core and volumes between magnesium containing layers and implanting the device in the posterior chamber would have been obvious from the teachings of Reiff et al. Therefore claims 1, 3-4, 6-8, 10-12, 15-16, and 18 are obvious over Imran in view of Aghion et al., Pryce et al., Reiff, and Varner et al. as evidenced by Wong et al. Claims 1, 3-4, 6-8, 10-12, 15-16, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Imran in view of Aghion et al., Pryce et al., Reiff, and Varner et al. as evidenced by Wong et al. as applied to claims 1, 3-4, 6-8, 10-12, 15-16, and 18 above, and further in view of Coppeta et al. (previously cited). Imran in view of Aghion et al., Pryce et al., Reiff, and Varner et al. as evidenced by Wong et al. render obvious the limitation of instant claims 1, 3-4, 6-8, 10-12, 15-16, and 18. The device can include an anti-VEGF compound, but a specific variety is not named. Coppeta et al. teach ranibizumab and bevacizumab as anti-VEGF antibodies known to be delivered by rod shaped, implantable drug delivery systems (see paragraphs 43 and 45-53 and figure 1-3; instant claim 6). They further envision the implants for use in the eye (see paragraph 99). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ ranibizumab or bevacizumab as the anti-VEGF compound/antibody in the device rendered obvious by Imran in view of Aghion et al., Pryce et al., Reiff, and Varner et al. as evidenced by Wong et al. and implanted in the eye for intraocular treatment. This modification would have been obvious in light of Coppeta et al. as the simple substitution of one known element for another in order to yield a predictable outcome. Therefore claims 1, 3-4, 6-8, 10-12, 15-16, and 18 are obvious over Imran in view of Aghion et al., Pryce et al., Reiff, and Varner et al., and Coppeta et al. as evidenced by Wong et al. Response to Arguments Applicant's arguments filed July 17, 2026 have been fully considered. In light of the amendment to the claims, the rejections under 35 USC 112 are hereby withdrawn. The remaining rejections are slightly adjusted to address the new claim limitations; however, the applicant’s arguments against the rejections under 35 USC 103 are unpersuasive. The applicant argues that each reference in the rejection does not teach an aspect of the instant product. These are not persuasive arguments since the combination of references is provided precisely because each reference does not separately teach all of the claimed limitations. These references represent what the artisan of ordinary skill would have had within their technical grasp or known at the time of the invention. Where one reference omits a pertinent teaching, another reference fills the void. For example, the applicant argues that Aghion et al. do not teach one hollow solid inscribed into another, yet Imran and Pryce et al. explicitly teach this configuration and are cited to highlight the recognition of this design’s utility by the prior art. The applicant also notes that Aghion et al. do not teach closing elements, yet Pryce et al. explicitly teach this component and the pointed end component 104 of Imran can be considered such a closing element/end cap as well. The applicant notes the absence of teachings concerning the instantly claimed configuration of components in arguing against Mao et al., yet these features are set forth by other cited references, while Mao et al. address the obviousness of a particular magnesium alloy instantly claimed. In response to applicant's argument that Aghion et al. teach a solid layer construct that is different than the liquid filled hollow concentric regions instantly claimed, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Imran teaches hollow concentric regions which they envision filled with therapeutic agent that may be in liquid or solid form. The combination of the teachings of Aghion et al. and Imran does not require that only their common features be applied in a resulting product. The applicant also argues that Pryce et al. teach that their end caps are fabricated separately and of a different material than the outermost cylinder of their drug delivery device, thus they do not compose a base of the outermost hollow solid. The description by Pryce et al. does not support this characterization. Both figure 5 and figure 7, which shows figure 5 in cross-section, shows the end caps 610 and 612 closing the ends of the concentric cylinders, including the hollow spaces between them (e.g., between elements 631 and 633), and having the same circumference as outermost element 631. The end caps form a base for all of the cylindrically shaped regions in the layered construct and meet the instant claim limitations of “forming a single closure element that simultaneously seals said core volume and said one or more crown volumes” PNG media_image4.png 481 923 media_image4.png Greyscale The radial release kinetics sought and obtained by the configuration of Pryce et al., and their emphasis of the higher resistance of the end caps to degradation/erosion than the walls, yield the same outcome instantly recited of sequential dissolution (see paragraphs 94, 153-155, and 160). Contrary to the applicant’s characterization, Pryce et al. do not teach that their end caps are required to be impermeable or non-erodible, but instead that they are “much less permeable or erodible” than the walls (see paragraph 153). The applicant argues that the rejection replaces the end caps of Pryce et al. with a degradable material, but this is not the modification that is made. The arrangement of Imran is modified in light of Pryce et al. in the rejection. Even if, semantically, the rejection replaced the end caps of Pryce et al. with a degradable material, this would be well within their contemplated embodiments. Pryce et al. exemplify the endcaps to be hydroxypropylmethyl cellulose which so a degradable material and explicitly state “the bulk of the dosage form may comprise a pharmaceutical excipient material that is subject to erosion or degradation upon immersion in a liquid such as water” (see paragraph 100; Ayer et al US Patent No. 4,915,952 column 4 lines 48-58). Furthermore, Pryce et al. include the same exemplary material in the endcaps (hydroxypropylmethyl cellulose) within the walls as well, but it is configured in a manner that has an increased rate of erosion due to the inclusion of a water soluble material (see paragraphs 100 and 153). Thus another degradable/erodible material, such as a magnesium or its alloy, would have been obvious to employ in the same role. The applicant argues that the pointed end cap of Imran does not seal internal volumes. While true, it sits at the end of their concentric nested (Russian doll) configuration of drug loaded hollow solids. Pryce et al. teach that a concentric nested arrangement and a concentric arrangement with concentric ends are obvious and known alternatives for obtaining serial drug layer release as well as the benefit of the latter. The application of a concentric ended arrangement to the structure of Imran is an obvious modification and yields its end cap sealing the internal volumes. There is no evidence of an unexpectedly superior outcome occurring due to the application of such a modification. Therefore this claimed arrangement remains obvious in light of the cited prior art. The applicant argues that there is no motivation to combine the cited prior art teachings. To the contrary, the motivation to combine the teachings is the overlap in subject matter concerning concentric designs for degradable layered drug delivery systems, as well as the utility of magnesium as a structural element in such systems. The applicant appears to argue that the only viable path to the combination of teachings in a prima facia case of obviousness is a teaching, suggestion, or motivation (TSM) explicitly provided by one of the source references. MPEP 2141(I) details that a reliance solely upon a TSM rationale is overly rigid and does not serve as the only route to a case of obviousness. Here the rationale based upon generally upon combining prior art elements according to known methods to yield predictable results, simple substitution of one known element for another to obtain predictable results, choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success, was employed to support the prima facia case of obviousness. These lines of reasoning are explicitly detailed as a viable path to building a prima facie case of obviousness (see MPEP 2141(III)). The applicant comments on each reference (e.g., Reiff et al., Varner et al., and Coppeta et al.) that is relied upon to further modify Imran in view of Aghion et al. and Pryce et al. as evidenced by Wong et al. so as to meet additional limitations. Each argument repeats arguments addressed above concerning the arrangement of components in the instantly claimed device. The response above is similarly reiterated. Conclusion No claim is allowed. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a). A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action. 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To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /CARALYNNE E HELM/Examiner, Art Unit 1615 /MELISSA S MERCIER/Primary Examiner, Art Unit 1615