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 .
Drawings
The drawings are objected to under 37 CFR 1.83(a) because they fail to show the release kinetics as described in the specification and depict data that was not previously in the disclosure. The text in the specification on page 30 lines 10-13 states “[t]he release rate of the systems with no PLL was 0.087 ± 0.044 mg/hr, and in 249 hours (10 days), about 87% of the total amount loaded of HA was released. The release rate of the systems with 10(w/v)% PLL as 0.055 ± 0.026 mg/hr, and in 249 hours (10 days), about 73% of the total amount loaded of HA was released”. It is not clear how the newly filed figure shows this outcome, given that the data points are quite linear. The stated rates imply much more spread, given their 50% level of error. Further, the data is completely different than that originally presented and thus constitutes new matter in that regard.
Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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.
Claims 1-6,10, 12, 14-16, and 20-21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1 and 12 recite “above the GT, the ophthalmic composition forms an optically clear hydrogel having a visible-light transmittance of at least 75% over wavelengths from about 500 nm to about 780 nm”. It is not clear if this recitation requires just one temperature above the gelation temperature to exist at which the recited visible light transmittance occurs or if the composition at any temperature above the gelation temperature must have the recited visible light transmittance. Yu B and the applicant, detail that polymers with the structural aspects instantly claimed, in solution of sufficiently high concentration to from a gel, transition from solution to gel then back to solution again, over the course of increasing temperature (see Yu et al. Macromolecular Research 2012 20(3): 234-243 – henceforth Yu B - page 237 second column first full paragraph-page 238 first column first partial paragraph and figure 3; instant specification page 28 line 26-page 29 line 4). The scope of compositions that overpower this phenomenon such that gel clarity is maintained “above the GT” is unclear.
The test apparatus recited in claims 1 and 12 for measuring release for the claimed composition is generically described as a microfluidic device that “resembles anatomical dimensions of both the anterior and posterior chamber of the human eye” that is run “under physiological flow conditions”. There is no indication as to how much resemblance to these regions of the eye is required or in which way(s) the dimensions are to be resembled. The anterior and posterior chambers have different sizes in the eye (see Edelman et al. US PGPub No. 2016/0158249 paragraph 2). Thus it is unclear what it means for one test region in a device to “resemble” both regions of the eye at the same time. As a result, the scope of the structure of the required testing device is not clear.
Claims that are not explicitly elaborated upon are also indefinite because they depend from an indefinite claim and do not add clarity. For the sake of application of prior art, the limitations at issue will be deemed as met by the prior art when the recited structure of the composition is met and both transparency at a temperature above the gelation temperature as well as release kinetics are addressed in the art. Clarification is still required.
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 1-6, 10, and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Yu B in view of in view of Sutariya et al. (US PGPub No. 2014/0271903), Rivers et al. (EP-2595604), and Lollo et al. (previously cited) as evidenced by Ensign et al. (previously cited) and the Polyethylene glycol MSDS (previously cited).
Yu B teaches a copolymer with an A-B-A block structure, wherein the A block is poly(D,L-lactic-co-glycolic acid) (PLGA), and the B block is polyethylene glycol (PEG) (page 234 second column last partial paragraph and page 235 second column first full paragraph; instant claim 1). They teach a PLGA-PEG-PLGA triblock copolymer gel compositions for drug delivery that have been employed for anti-tumor treatment (see abstract and page 234 second column). They explore nuances of this polymer in a preparation composed of a model drug, PLGA-PEG-PLGA, and phosphate buffer (pharmaceutically acceptable carrier (see page 234 second column last partial paragraph and page 235 second column last partial paragraph; instant claim 1). They detail preparing two versions of very similarly composed polymers that differ in regard to the synthesis temperature for the PLGA blocks. Solutions of the polymer at adequate concentration undergo a transition to gel with increasing temperature that have an embedded transition from an initially transparent gel to an opaque gel then back to a solution (see page 237 second column first full paragraph-page 238 first column first partial paragraph and figure 3). The polymer synthesized at higher temperature, called Polymer-160, has a narrower temperature span over which gel occurs and a higher temperature at which the gel transitions to opaque than the polymer made at lower temperature and called Polymer-130 (see figures 1 and 3). The polydispersity of Polymer-160 polymers is 1.21, the gelation temperature at 10-20 wt% polymer is about 30 to 35⁰C, the molar ratio of lactide to glycolide is 15/1, the average molecular weight of the PEG is 1500 Da, and the average molecular weight of each PLGA block is 1714 (see table 1 and figure 3; instant claims 1-3). The polydispersity of Polymer-140 polymers is 1.19, the gelation temperature at 10-20 wt% polymer is about 25 to 30⁰C, the molar ratio of lactide to glycolide is 15/1, the average molecular weight of the PEG is 1500 Da, and the average molecular weight of each PLGA block is 1650 (see table 1 and figure 3; instant claims 1-3). This yields a weight ratio of PLGA to PEG of 2.28/1 and 2.2/1 for the Polymer-160 and Polymer-130, respectively (see instant claim 1). Given a density of PLGA of 1.2 g/ml, a density of PEG of 1.1-1.2 g/ml, and presuming the model active contribution of 10 mg/ml is negligible (density equal to 1) due to its small proportion, the PLGA-PEG-PLGA present in the 10 to 20 wt% polymer preparation corresponds to about 10.7 to 20.7% w/v PLGA-PEG-PLGA (see figure 3, Ensign et al. paragraph 222 and the Polyethylene glycol MSDS; as calculated by the examiner; instant claim 4). Yu B teaches the release of the model active to surpass 40 days, where at day 18 and a 10 mg/ml drug loading, a 20 wt% gel has released about 40% of the initial load (see figure 9). Polymer-160 releases at a higher rate than Polymer-130 after 18 days (see figure 9). Extension of the displayed rate of release implies that release would still be occurring at 2 months and 4 months (see instant claim 1). The presence of poly(L-lysine) is not detailed nor is the presence of a nucleic acid conjugate.
Sutariya et al. teach a thermosensitive PLGA-PEG-PLGA triblock copolymer for controlled release of a desired drug active in the eye (see abstract and paragraphs 15, 19-21, and 39). The polymer is not limited so long as it has thermosensitive characteristics and is exemplified to have a 1500 Da PEG block and DL-lactide polymerized with glycolide to provide a 2:1 ratio of PLGA to PEG (see example 1). When assessed, various concentrations of the polymer in aqueous solution between 10 and 35 %w/v yielded a gelation temperature of about 37⁰C (see paragraph 58 and figure 1).
Rivers et al. teach of the release of small interfering RNA (siRNA), as eye treatments, from a biodegradable polymer envisioned to include PLGA or its monomers, where one of two excipients envisioned as polylysine or spermidine is included to slow the initial burst and slow the overall release of siRNA from the polymer (see paragraphs 11, 28, and 66). They teach the excipient present at 1 to 15 wt% and the siRNA may be released for one or more months (see paragraphs 69-70). They further detail that the excipient may also enhance cell uptake of the siRNA into the cell (see paragraph 80).
Lollo et al. teach poly (L-lysine) as a polycationic complexing agent to pair with polynucleotides for delivery to improve their expression (see abstract and column 7 lines 33-37). They teach that their poly (L-lysine) has an average molecular weight of 3,800 to 60,000 Da, where 17,000 Da is preferred (see column 7 lines 43-49). They additionally teach that desirable polynucleotides are envisioned to include antisense and detail the modification of the polynucleotides with one or more diol terminal groups (nucleic acid conjugate) to protect against nuclease activity (see column 5 line 44-column 6 line 16). Lollo et al. also teach a conjugate polycationic agent that has a cell surface binding ligand, such as an antibody, bound to the poly(L-lysine) and that such conjugates further improve the expression of the complexed polynucleotide (see column 6 lines 17-31 and 40-47 and column 18 line 50-column 19 line 28).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to add a poly(L-lysine) complexed siRNA conjugate for eye treatment to the Polymer-160 PLGA-PEG-PLGA of Yu B. This modification would have been obvious in light of Sutariya et al. and Rivers et al. who detail the utility of PLGA containing or PLGA-PEG-PLGA polymers for delivery of therapeutics to the eye. In addition, Rivers et al. detail polylysine to provide low burst, slowed sustained delivery of siRNA as a therapeutic for this locale. Lollo et al. teach the L enantiomer of polylysine for this use as well as conjugation of protective terminal groups to the end of a therapeutic polynucleotide. Thus poly(L-lysine) and an siRNA of Rivers et al. with terminal modification as detailed by Lollo et al. would have been obvious to include in the polymer of Yu B as the application of the same technique to a similar product in order to yield the same improvement and as the simple substitution one known element for another in order to yield a predictable outcome. Application of the proportions of polylysine detailed by Rivers et al. would follow and overlap with or embrace the poly(L-lysine) at about 10 to about 50% w/v (about 0.1 mg/ml to about 0.5 mg/ml), the about 20 %w/v (about 0.2 mg/ml), and the about 10%w/v instantly claimed, thereby rendering the instantly claimed ranges obvious (as calculated by the examiner). “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed.Cir. 1990)” (see MPEP 2144.05).
Given the temperature dependent transparent to opaque transition for the PLGA-PEG-PLGA polymers, it is the position of the examiner that a temperature exists, just above the gelation point, where a gelling solution of the polymer-160 of Yu B within the instantly claimed range (e.g., about 10 to 20% w/v) yields a transparent gel and permits light transmittance as instantly recited, absent evidence to the contrary. The modified matrix with poly(L-lysine) would be expected to still provide its demonstrated release rate and fulfill the instantly claimed release kinetics at 1 month and likely also at 2 months and 4 months. According to MPEP 2145II, mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979). In addition, the fact that an inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). The composition that is rendered obvious contains all the claimed components at the claimed proportions. In addition, the PLGA-PEG-PLGA has the same PEG molecular weight, PLGA composition, and differs by very little in regard to the PLGA to PEG ratio and PLGA molecular weight as compared to instant polymer B4 which is illustrated to have the recited light transmittance in solution when present at 10 to 25% w/v at some test temperature (see instant table 1. Thus, the modified composition of Yu B would carry the properties linked to this polymer and the other claimed materials (see instant claim 1). Therefore claims 1-6, 10, and 20-21 are obvious over Yu B in view of in view of Sutariya et al., Rivers et al., and Lollo et al. as evidenced by Ensign et al. and the Polyethylene glycol MSDS.
Claims 1-6, 10, 12, 14-16, and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Yu B in view of in view of Sutariya et al., Rivers et al., and Lollo et al. as evidenced by Ensign et al. and the Polyethylene glycol MSDS as applied to claims 1-6, 10, and 20-21 above, and further in view of Yu et al. (Biomaterials Science 2013 1:411-420 – previously cited) and Hughes et al. (US PGPub No. 2008/0268051).
Yu B in view of in view of Sutariya et al., Rivers et al., and Lollo et al. as evidenced by Ensign et al. and the Polyethylene glycol MSDS render obvious the limitations of instant claims 1-6, 10, and 20-21. In addition to poly(L-lysine), Lollo et al. also teach a conjugate polycationic agent that has a cell surface binding ligand, such as an antibody, bound to the poly(L-lysine) and that such conjugates further improve the expression of the complexed polynucleotide (see column 6 lines 17-31 and 40-47 and column 18 line 50-column 19 line 28; instant claim 12). Most of the limitations of instant claims 12 and 14-16 are met by Yu B in view of in view of Sutariya et al., Rivers et al., and Lollo et al. as evidenced by Ensign et al. and the Polyethylene glycol MSDS except for in regard to doxorubicin in the composition.
Hughes et al. teach a composition for treatment of the eye that includes an anti-angiogenesis active (see abstract). They explicitly envision anti-angiogenesis actives to include siRNA and also detail a gel composition form (see paragraph 135 and claims 3 and 9). They further teach combining other drug compounds with the anti-angiogenic active and doxorubicin is amongst those that are envisioned (see paragraph 178).
Yu et al. teach compositions for drug delivery composed of composed of doxorubicin, PLGA-PEG-PLGA, and phosphate buffer (pharmaceutically acceptable carrier) (see abstract, page 412 second column first paragraph, and page 413 first column first full paragraph; instant claim 12).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ an antibody conjugate version of poly(L-lysine), as taught by Lollo et al., as the polylysine of Yu B in view of in view of Sutariya et al., Rivers et al., and Lollo et al. as evidenced by Ensign et al. and the Polyethylene glycol MSDS to yield further antisense expression improvement. This modification is also obvious as the application of the same technique to a similar product in order to yield the same improvement. Maintenance of the relative proportion of the polycation in the complex based on the poly(L-lysine) portion of the conjugate in the complex would follow (see instant claims 12 and 16). It additionally would have been obvious to add doxorubicin to the composition in light of Yu et al. who teach this compound was already known to be delivered from PLGA-PEG-PLGA gels and Hughes et al. who suggest its utility with a siRNA for the eye. This modification is also obvious as the application of the same technique to a similar product in order to yield the same improvement. Therefore claims 1-6, 10, 12, 14-16, and 20-21 are obvious over Yu B in view of Sutariya et al., Rivers et al., Lollo et al., Yu et al., and Hughes et al. as evidenced by Ensign et al. and the Polyethylene glycol MSDS.
Response to Arguments
Applicant's arguments filed March 30, 2026 have been fully considered. In light of the amendment to the claims, the previous grounds of rejection are hereby withdrawn. New grounds of rejection are detailed to address the new claim limitations.
The applicant argues against Yu et al. providing a hydrogel with the instantly claimed transmittance properties. More specifically, they argue that an unexpected property may cause what appears to be an obvious composition to be nonobvious. However, transparency is not an unexpected occurrence in PLGA-PEG-PLGA aqueous gels as detailed by Yu B. The polymer of Yu et al. meets the structural limitations of instantly claim 1, and would be expected to exist in aqueous gel form that is transparent at some concentration and temperature. However, the range of temperature over which a transparent gel occurs would have be inferred based on the understanding of Yu B.
A showing of an unexpected outcome is possible in spite of the understanding of transparency occurring in PLGA-PEG-PLGA hydrogels. For example, if the degree of transparency is linked to a particular disclosed polymer architecture in an unobvious way or to the addition of other components in an unobvious manner, such evidence and a commensurate claim scope could provide secondary considerations pointing away from obviousness.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CARALYNNE E HELM whose telephone number is (571)270-3506. The examiner can normally be reached Mon-Fri 9-5.
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/CARALYNNE E HELM/ Examiner, Art Unit 1615
/MELISSA S MERCIER/ Primary Examiner, Art Unit 1615
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