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 .
Status of the Claims
Claims 1-11 are pending.
Claims 1-8 are withdrawn from consideration as directed to a non-elected invention.
Claims 9-11 are presented for examination and rejected as set forth below.
Claim Interpretation
Applicants claims are directed to methods of treating an anterior segment eye disease by the administration of a hollow nanosphere formed from any of a Markush-type listing of alternative metal oxides, to the surface of which is grafted a poly-L-histidine and an ophthalmic drug. Dependent claims specify a Markush-type listing of alternative eye diseases to be treated, with Claim 11 specifying that the composition used in the method is one for intraocular or topical administration.
Response to Amendment
The Declaration of inventors Lai and Yang under 37 CFR 1.132 filed 16 January 2026 is insufficient to overcome the rejection of claims 9-11 based upon the combined teachings of McDonnell, Bhatia, and Huang as set forth in the last Office action because the evidence provided and discussed does not represent an achievement of a result the skilled artisan would consider unexpected.
The data presented by the declaration of Lai and Yang establishes that the L-histidine coated hollow nanoparticles according to the present claims are more effective in the treatment of various anterior segment eye disorders, as evidenced by data tending to show significant decreases in mRNA expression of inflammatory cytokines, as well as data appearing to establish significant improvement in corneal healing when compared to not only negative controls, but solid L-histidine coated nanoparticles used as drug delivery carriers. On this basis, declarants Lai and Yang assert, sufficient secondary indicia of nonobviousness has been shown to overcome the Examiner’s prima facie case of obviousness.
To be sure, once a prima facie case of obviousness is established, the burden shifts to the applicant to come forward with arguments and/or evidence to rebut the prima facie case. In re Dillon, 919 F.2d 688, 692, 16 USPQ2d 1897, 1901 (Fed. Cir. 1990). However, Applicants are reminded that any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). “[A]ppellants have the burden of explaining the data…they proffer as evidence of non-obviousness.” Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd. Pat. App. & Inter. 1992). The evidence relied upon should establish “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.” Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992).
Here, the Examiner cannot agree that the data Applicants have provided establishes the improvement in treatment afforded by the use of hollow versus solid nanoparticulate drug delivery constructs, otherwise identical in formulation, is unexpected. Xing (Ruijin Xing, et al, Hollow Iron Oxide Nanoparticles as Multidrug Resistant Drug Delivery and Imaging Vehicles, 6 Nano. Res. 1 (2013)) establishes that hollow drug delivery nanoparticles can load and delivery more drug than solid counterparts (Abs.), and Yang (Ya-Huei Yang, et al, Hollow Mesoporous Hydroxyapatite Nanoparticles (hmHANPs) with Enhanced Drug Loading and pH-Responsive Release Properties for Intracellular Drug Delivery, 1 J Mater. Chem. B 2447 (2013)), which establishes that the interior of hollow nanoparticles serves as a drug reservoir, increasing the drug loading capacity thereof. (2447). By virtue of the known capacity of hollow nanoparticles to incorporate, and therefore delivery, higher doses of drugs to targeted tissues than otherwise identical solid nanoparticles, the fact that improved therapeutic outcomes are associated with hollow nanoparticles cannot be said to be unexpected. “Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof.” In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967), see also In re Skoner, 517 F.2d 947, 950 (CCPA 1975).
For at least these reasons, the Declaration of Lai and Yang is unpersuasive.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 9-11 are rejected under 35 U.S.C. 103 as being unpatentable over McDonnell (WO2011/106702), in view of Bhatia (WO2008/073856), and Huang (Wenjuan Huang, et al, Hexahistidine-Metal Assemblies: A Promising Drug Delivery System,90 Acta Biomat. 441 (2019)).
McDonnell describes the treatment of eye disorders by the administration to the eye of a composition containing a coated particle and a therapeutic agent. (Abs.; Pg.5-6). McDonnell indicates that topical as well as intraocular routes of administration fall within the scope of this treatment. (Pg. 26). Metal oxide nanometer sized particles fall within the scope of the core particles of the McDonnell disclosure. (Pg.7). Therapeutic agents to treat keratitis and uveitis are described by McDonnell as useful embodiments of the methods described. (Pg.15).
Despite describing the treatment of keratitis or uveitis by the topical or intraocular administration of compositions containing coated metal nanoparticles and active agents for the treatment of keratitis or uveitis, McDonnell does not describe using hollow nanoparticles of any of the metal oxides recited by Claim1, nor is a polyhistidine coating required by the present claims recited.
Bhatia also describes nanoparticulate drug delivery constructs for the use in the treatment of disease. (Abs.). Ophthalmic formulations such as eye drops fall within the scope of the compositions described by Bhatia. [00316]. Hollow metal oxide nanoparticles, such as Iron III and Copper II oxides of Claim 1 having a polymeric coating layer to improve biocompatibility are described by Bhatia as useful in these methods and compositions. [00122; 00124; 00132; 00143; 00149]. Bhatia indicates that the hollow metal nanoparticles are compatible with a wide variety of active agents suitable for formulation and delivery by the compositions and methods described. [00229].
The art therefore establishes that diseases such as keratitis or uveitis may be treated by the topical or intraocular administration of compositions containing coated metal nanoparticles and active agents for the treatment of keratitis or uveitis. The art also establishes that hollow metal oxide nanoparticles of each of the Iron III and Copper II oxides of Claim 1 may be coated by polymers to improve biocompatibility for drug delivery purposes, but does not specify the particular use of a poly-L-histidine as such a biocompatible coating.
This is cured by the teachings of Huang, which indicates that coating metal nanoparticles with polyhistidine improves drug loading, biocompatibility, and drug uptake from the nanoparticles so coated. (Pg.447, 451). While silent as to the particular isomers of histidine used, the skilled artisan would recognize the L isomers of amino acids are the naturally occurring isomers and would therefore at once envisage the polyhistidine of the Huang reference as the naturally occurring isomer absent an indication to the contrary.
Because of the known ability of polyhistidine coating on metal nanoparticles to improve drug loading, biocompatibility, and drug uptake from metal nanoparticles so coated, as well as the known utility of polymer-coated hollow Iron III and Copper II oxide nanoparticles as drug delivery constructs, the skilled artisan would have found it prima facie obvious to provide the hollow Iron III and Copper II oxide nanoparticles of Bhatia with polyhistidine as the polymeric coating, and used these nanoparticles as the drug delivery constructs in the methods of McDonnell to treat keratitis or uveitis. This is because “[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious.” KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976)). “[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious,” the relevant question is “whether the improvement is more than the predictable use of prior art elements according to their established functions.” (Id.).
Response to Arguments
Applicant's arguments filed 16 January 2026 have been fully considered but they are not persuasive.
Applicants assert that McDonnell fails to teach a nanosphere per the present claims, and that various specific examples described are different from the subject matter of the present claims. Applicants assert Bhatia fails to teach or suggest the difference in efficacy between solid and hollow nanospheres, and that Huang merely describes histidine coatings on particles rather than the histidine coated hollow particles of the claims.
Applicants are reminded that it is not possible to establish the non-obviousness of an invention rendered obvious by the combined teachings of multiple prior art references by arguing that each of the references relied upon fails to teach the entirety of the invention which has been claimed; the absence of a single anticipatory reference is implied by both the reliance on the combined teachings of multiple references as well as the fact that the rejection being made is one of obviousness under 35 U.S.C. 103 rather than any of the subsections of 35 U.S.C. 102. MPEP § 2145(IV), see In re Keller, 642 F.2d 413, 426 (C.C.P.A. 1981) (citing Application of Young, 403 F.2d 754, 757 (C.C.P.A. 1968) (indicating that "[O]ne cannot show non-obviousness by attacking references individually where ... the rejections are based on combinations of references"). As applicants have not presented argument or evidence that the Examiner’s reasoning and rationale for combining the art in the manner set forth previously and again above falls short of the standard of obviousness, these arguments are unpersuasive. In re Lovin, 652 F.3d 1349, 1357 (Fed. Cir. 2011) (“[T]he Board reasonably interpreted Rule 41.37 to require more substantive arguments in an appeal brief than a mere recitation of the claim elements and a naked assertion that the corresponding elements were not found in the prior art.”).
As set forth above, the Declaration of Lai and Yang is unpersuasive.
Conclusion
No Claims are allowable.
THIS ACTION IS MADE FINAL. 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 SEAN M BASQUILL whose telephone number is (571)270-5862. The examiner can normally be reached Monday through Thursday, 5:30 AM to 4 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ali Soroush can be reached at (571) 272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SEAN M BASQUILL/Primary Examiner, Art Unit 1614