DETAILD 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 .
Election/Restrictions
To summarize the current election, the applicant elected Group I where the amphiphilic polymer is polyethylene glycol-b-poly(hydroxylpropylmethacrylamide-oligolactate) and the nanoparticle surface comprises a glycoprotein targeting moiety that comprises boronic acid with traverse.
The requirement is still deemed proper and is therefore made FINAL.
Claim 10 recites R2 as “optionally substituted alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl”. The applicant included this claim in the listing of those the read on the elected species. It is not clear how the elected substituent containing an isopropyl bound to oligolactate is embraced by this listing. However, it may be possible that some interpretation of this recitation embraces the elected species, thus claim 10 has been retained amongst the examined claims. Claim 17, however, recites R1 as “hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl" with no mention of substitutions. Thus boronic acid containing substituents are not embraced and the elected polymer is not within the scope of claim 17 or its dependent claim 18.
Claims 17-18, 49-50, 52, and 54-55 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention and species, there being no allowable generic or linking claim.
The applicant is reminded to update their claim status identifiers to reflect the status of the claims in light of the restriction
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 10 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 10 recites R2 as “optionally substituted alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl”. The layered definition of the terms ”substituted” and “substituent” where each substituent could itself be substituted make the boundary on the permissible moieties unclear because it is difficult to discern which chemical moieties are included. For the sake of compact prosecution and the application of prior art, the elected polymer will be interpreted as fulfilling a substituted alkyl for this moiety. 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 1-3, 6, 8, 10, 13-14, 26-27, 30, and 61 are rejected under 35 U.S.C. 103 as being unpatentable over Soga et al. (previously cited) in view of Zhao et al. (previously cited), Du et al. (previously cited), Sapino et al. (Nanomaterials 2019 884(9): 1-19), Gumus et al. (Clinical Ophthalmology 2009 3:57–67), Boboridis et al. (Expert Opinion on Pharmacotherapy 2018 19(9):1027-1039), and Bandyopadhyay et al. (US PGPub No. 2002/0107238) as evidenced by Davis et al. (US Patent No. 5,192,535).
Soga et al. teach degradable thermosensitive polymer micelles for delivery of hydrophobic drugs, particularly for tumor and inflammation treatment (see abstract and page 938 second column and figure 1; instant claims 1 and 27). The polymer is a diblock copolymer of poly(ethylene glycol) (PEG) and poly(hydroxypropylmethacrylamide-oligolactate) (pHPMA-DL), where the oligolactate polymer has 2 units of lactate as shown below:
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(see Scheme 1; instant claims 3, 6, 10, and 13). According to the instant nomenclature, Y = NH, R3 = alkyl, R2 = substituted alkyl (see instant claim 10). They detail the polymerization as the product of the PEG macroinitiator
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reacted with hydroxypropylmethacrylamide dilactate (see scheme 1). Soga et al. teach the number average molecular weight of the PEG block as 5000 Da while the pHPMA-DL block is 3000 Da, 6900 Da or 13,600 Da (see page 9389 second column first partial paragraph, and table 1; instant claims 6, 8, and 13-14). According to the instant nomenclature, these sizes correspond to n ≈ 24, 48, or 114, respectively (see instant claims 6 and 13). The micelle size resulting from these polymers varied between 50 and 80 nm (see figure 5). Soga et al. teach that micelles of the polymer form at temperatures beyond the 10⁰C cloud point of the pHPMA-DL block which governs the micelle formation of the polymer (see page 9391 fist column last partial paragraph-second column). The micelles are destabilized over time under physiological conditions at 37⁰C due to hydrolysis of the lactate groups that raises the cloud point and serves as a sustained release mechanism for contained drug (see page 9389 first column and page 9394 second column last partial paragraph). A terminal boronic acid containing group is not detailed nor is the inclusion of the nanoparticles in an anionic polymer containing aqueous medium.
Gu et al. teach mucoadhesive nanoparticles composed of amphiphilic polymer conferred with this adhesive property due to the presence of targeting moieties on the polymer that arrange on the surface of the nanoparticles (see abstract). They teach the polymer as a block copolymer with a hydrophobic block and hydrophilic block, where the hydrophilic contains phenylboronic acid moieties as the targeting moieties that attach to the mucosa (see paragraphs 16-18). Relevant application locales for such nanoparticles include the eye, where topical application of compounds such as cyclosporine is envisioned for addressing keratoconjunctivitis sicca (see paragraphs 9 and 162-165; instant claim 27).
Sapino et al. teach of the recognized utility of thermosensitive drug delivery systems for ocular therapies (see abstract and table 2). Gumus et al. teach that keratoconjunctivitis sicca is an inflammatory condition and Boboridis et al. teach that cyclosporine is a hydrophobic drug (see page 1029 fist column first full paragraph).
Zhao et al. teach drug delivery micelles composed of amphiphilic block copolymers that include an amphiphilic compound/polymer with a PEG block and oligomethylene block (PEG monostearate) (see abstract). The PEG is provided with a terminal phenylboronic acid as a targeting moiety that is positioned on the surface of the micelle upon self-assembly (see scheme 1 page 14845 second column last partial paragraph-page 14846 first full paragraph). The conjugation of phenylboronic acid occurs at an end of PEG bearing a hydroxyl group (see abstract, scheme 1, page 14846 second column last full paragraph-page 14847 first column first partial paragraph).
Du et al. teach the preparation of block copolymers of PEG and an acrylamide-containing monomer (see abstract.). They employ a similar PEG macroinitiator as Soga et al. except its PEG portions are terminated by hydroxyl functional groups as shown below:
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.
Bandyopadhyay et al. teach of the inclusion of crosslinked polycarbophil in an ocular composition configured as drops as an ophthalmic excipient that reduces the rate of removal of the composition from the eye (see abstract and paragraphs 49, 104, and 147-149). Polycarbophil is a crosslinked polyacrylic-acid polymer which is polymer with a repeat unit of
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(see Davis et al. example IX; instant claim 61).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare cyclosporine loaded nanoparticle micelles from the polymer of Soga et al. with a phenylboronic acid terminal group on the PEG block for topical application to address inflammation in the eye. This modification would have been obvious because Soga et al. provide a temperature sensitive drug delivery systems and Sapino et al. teach the utility of temperature sensitive drug delivery systems for the eye. Further, Soga et al. teach their hydrophobic drug containing particles for treating inflammatory conditions and Gu et al. teach topical treatment of keratoconjunctivitis sicca, an inflammatory condition, with cyclosporine, a hydrophobic drug. Thus the configuration of the nanoparticle micelles of Soga et al. for addressing an inflammatory condition with cyclosporine in the eye would have been obvious. The choice of cyclosporine is obvious as the simple substitution of one known element for another in order to yield a predictable outcome (e.g., generic anti-inflammatory drug vs. specific anti-inflammatory drug). Gu et al. further teach the desirable mucoadhesive property conferred to amphiphilic polymer based nanoparticles that can carry cyclosporine for the eye via the presence of phenylboronic acid groups on their surface. Zhao et al. teach phenylboronic acid terminated PEG blocks as an avenue to provide phenylboronic acid targeting moieties on the surface of nanoparticles composed of an amphiphilic diblock copolymer with a PEG block like the polymer taught by Soga et al. The addition of the phenylboronic acid terminal groups to the polymer of Soga et al. would then have been obvious as the application of the same technique to a similar product in order to yield the same improvement. Du et al. and Zhao et al. demonstrate that the necessary connective chemistry was already known in the art and would have been obvious to apply to facilitate the modification. In addition, it would have been obvious to include the drug loaded nanoparticle micelles in a polycarbophil containing drop formulation as detailed by Bandyopadhyay et al., where their drug is encapsuled in the micelles. This modification also would have been obvious as the application of the same technique to a similar product in order to yield the same improvement (e.g., longer retention on the eye). Therefore claims 1-3, 6, 8, 10, 13-14, 26-27, 30, and 61 are obvious over Soga et al. in view of Zhao et al., Du et al., Sapino et al., Gumus et al., Boboridis et al., and Bandyopadhyay et al. as evidenced by Davis et al.
Response to Arguments
Applicant's arguments filed April 27, 2026 have been fully considered. In light of the amendment to the drawings and claims, the objection to the drawings and the rejection of claims 13-14, 26, and 30 under 35 USC 112(b) and double patenting rejections are hereby withdrawn. The amendment to the claims necessitates a new rejection under 35 USC 103 to address the new limitations. Applicant’s arguments are not persuasive in regard to the rejection of claim 10 under 35 USC 112(b) and the obviousness of modifying the polymer of Soga et al. with a terminal boronic acid.
Regarding the rejection under 35 USC 112(b):
The applicant argues that the scope of “optionally substituted” is clear. To the contrary, the applicant has stated in the response to the restriction requirement that claim 10 reads on the election of species that requires the hydrophobic block of the amphiphilic polymer to be poly(hydroxylpropylmethacrylamide-oligolactate). This would require the R2 of claim 10 to be
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where the “*” indicates a point of attachment and p is an integer. It is not clear how this structure is embraced by “optionally substituted alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl”. While the first portion following the point of attachment is an alkyl, it is not at all clear how the oligolactate portion qualifies as a “substitution” as the instant specification defines them on pages 20-26. Consequently the scope of claim 10 remains unclear.
Regarding the rejection under 35 USC 103:
The applicant argues that the terminal substitution on the PEG block of Soga et al. is a methyl and thus one of ordinary skill would not have had a reasonable expectation of success to modify it with a phenylboronic acid due to unpredictability in the impact of a terminal acid group as opposed to a methyl group would have on the cloud point. The applicant offers no evidence to support this argument. Soga et al. discuss that the nature of the pHPMA-DL block controls the cloud point of their polymer, as noted in the rejection. Further Lee et al. teach of the thermosensitivity of a copolymer composed of isopropylacrylamide, acrylic acid, and hydroxyethyl methacrylate (di)lactate (Polymer International 2005 54:418-422). Hydroxyethyl methacrylate (di)lactate is a monomer similar to the instant hydroxylpropylmethacrylamide-oligolactate and the HPMA-DL of Soga et al.. The presence of acid groups more numerous than a single terminal group shifted the cloud point (lower critical solution temperature/LCST) of the polymer, but the impact was an increase in value that remained below 37⁰ C as the amount of acid increased while the post-hydrolysis cloud point remained static and above 37⁰ C (see table 2). Thus the addition of one terminal acid group per polymer chain on the polymer of Soga et al. would not be expected to alter the cloud point behavior of the polymer in fashion that alters the concept of how it functions. Consequently, there is no evidentiary support of record that a reasonable expectation of success was lacking for the modification set forth in the rejection.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Wax can be reached at (571) 272-0623. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CARALYNNE E HELM/Examiner, Art Unit 1615
/MELISSA S MERCIER/Primary Examiner, Art Unit 1615
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