DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/24/2025 has been entered.
AIA Status of the Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Arguments
Applicant’s arguments, filed 7/24/2025, have been fully considered.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. In particular, the rejection of claims under 35 U.S.C. 112(b) is WITHDRAWN in view of Applicant’s amendments to the claims.
Applicant traverses the rejection of claims under 35 U.S.C. 103(a). Applicant first notes that “Wei teaches an ophthalmic composition that includes lipid nano-dispersions that are stabilized by oil-phase and aqueous-phase emulsifiers and suspended in a gel substrate” which “is structurally different from the claimed invention, with Wei’s solid lipids ‘entrapped’ in the liquid lipids” (Applicant Arguments, Page 6). As argued by Applicant, although “Wei teaches that ‘the ophthalmic composition of the present invention can be used for prevention or treatment of dry eye syndrome without containing any active pharmaceutical agent’… Wei explicitly teaches that this possibility is a result of the structure used” and “[t]here is no suggestion in Wei that a similar benefit might be obtained through different architectures” (Applicant Arguments, Page 6).
It is agreed that, as discussed in the basis of the rejection, the lipid nano-dispersion/solid lipid nanoparticle taught by Wei et al is structurally different from the instantly claimed nanostructured lipid carrier. However, it is not found persuasive that Wei et al “explicitly teaches” that said nano-dispersion/solid lipid nanoparticle structure is required “for prevention or treatment of dry eye syndrome without containing any active pharmaceutical agent”. Rather, discussing the ability of “nanostructured lipid carrier[s]… to deliver… lipophilic drug to the eye to improve the bioavailability of the active drug”, Wei et al indicates only that “it is not known to the inventors whether there is any report of using the nanostructured lipid carrier matrix to treat the dry eye disease” (Paragraph 0066).
Moreover, the rejection is based further on Seyfoddin et al (which teach that “SLNs can be successfully converted to physically superior NLCs” (Abstract)) and Viladot Petit et al (which specifically disclose NLCs comprising a solid lipid out shell comprising cholesterol and a liquid lipid inner core comprising castor oil).
Applicant, however, argues that “Seyfoddin discusses the advantages of NLCs specifically within the context of ocular drug delivery rather than asserting universal superiority of NLCs” (Applicant Arguments, Page 7). That is, Seyfoddin et al “does not teach superiority of NLCs over other structures generally… only when a drug is involved” (Applicant Arguments, Page 7).
The argument is not found persuasive. At the outset, as discussed in the basis of the rejection, Seyfoddin et al teach that NLCs “are structural modifications of SLNs developed to address their insufficiencies, such as… stability problems” (Page 513, Column 1). The improvement in stability relative to SLNs taught by Seyfoddin et al is understood as an improvement in physical stability of the NLC itself, independent of any drug involved.
Furthermore, as discussed by the instant Specification, “[t]he triglyceride, such as castor oil or oils of similar triglyceride component, can advantageously provide anti-inflammatory properties” as well as “reduce the evaporation of tears from the eye and may be used to treat dry eye disorders such as Meibomian gland dysfunction, due to their anti-inflammatory action” (Paragraph 0008). Indeed, as taught by Hazarbassanov (Investigative Ophthalmology & Visual Science, 55:3684, 2014) and Maissa et al (Contact Lens & Anterior Eye 33:76-82, 2010) – both of which are being applied solely in response to Applicant’s arguments and not as a basis of the rejection – castor oil itself is active in the treatment of dry eye. In particular, as taught by Hazarbassanov, “topical castor-oil lubricant… led to significant improvement in symptoms such as dryness” (Results). And, as taught by Maissa et al, “castor oil eyedrops achieved a residence time of at least four hours post-instillation and produced a more stable tear film and an associated decrease in ocular symptoms over the entire 4 h follow-up period for the symptomatic patients” suffering from dry eye (Page 81, Column 2). Accordingly, even if one were to limit Seyfoddin et al as teaching the “superiority of NLCs over other structures… only when a drug is involved” (Applicant Arguments, Page 7), it is evident that castor oil would be considered “a drug” in the treatment of dry eye.
Applicant next argues that “even if the teachings of Wei, Seyfoddin, and Viladot Petit are combined, there is no reasonable expectation of success in treating dry eye disorder with a blank NLC as claimed” (Applicant Arguments, Page 7). As argued by Applicant, although Wei et al teach that the disclosed compositions “can be used for prevention or treatment of dry eye syndrome without containing any active pharmaceutical agent” (Paragraph 0058), “Wei does not provide any explanation of the underlying mechanism or supporting data regarding this effect” (Applicant Arguments, Page 7).
Yet, Wei et al need not teach “the underlying mechanism” by which a SLN comprising castor oil treats dry eye for a person of ordinary skill in the art to reasonably predict that a NLC based thereon would similarly treat dry eye. Moreover, as discussed above, it was known at the time the invention was made that “[t]he triglyceride, such as castor oil or oils of similar triglyceride component, can advantageously provide anti-inflammatory properties” as well as “reduce the evaporation of tears from the eye and may be used to treat dry eye disorders such as Meibomian gland dysfunction, due to their anti-inflammatory action” (Specification, Paragraph 0008).
Lastly, Applicant argues that the present invention “demonstrates the unexpected result that a drug-free NLC, through its specific structure and composition, suppresses inflammatory cytokines” (Applicant Arguments, Page 8). As argued by Applicant, the data “ties the therapeutic effect specifically to the presence of cholesterol within the NLC formulation, not to cholesterol per se” and the assumption that the compositions of Wei et al, comprising “similar components will lead to a similar effect… is unfounded. There is no indication that Wei suppresses inflammatory cytokines” (Applicant Arguments, Page 8).
In particular, Applicant provides an updated Declaration under 1.132 by Dr. Laurence Fitzhenry which states that “the use of cholesterol in NLCs… surprisingly reduce cytokine secretion (MMP-9)” (Paragraph 8). Additionally, the Fitzhenry Declaration demonstrates that “cells treated with blank cholesterol-containing NLCs (no drug) reduce cytokine secretion in HCECs that have been induced for inflammation by lipid polysaccharide (LPS) complex treatment” (Paragraph 10) and that “[r]educed cytokine secretion (MMP-9, IL-6 and TNF-α) was observed when treated with blank NLCs” (Paragraph 12). As argued the by the Fitzhenry Declaration, “it is this result of the blank NLCs that is a surprising result as there is no known anti-inflammatory agent included” (Paragraph 12).
The argument is not found persuasive. It is maintained that the lipid nanoparticles of Wei et al (US 2016/0074321) comprising wool fat (which comprises cholesterol) would, presumably, also reduce cytokine secretion. Furthermore, the NLCs evaluated by Applicant in the instant Specification and in the Fitzhenry Declaration further comprise castor oil, as do the lipid nanoparticles of Wei et al. And, as discussed above, “[t]he triglyceride, such as castor oil or oils of similar triglyceride component, can advantageously provide anti-inflammatory properties” as well as “reduce the evaporation of tears from the eye and may be used to treat dry eye disorders such as Meibomian gland dysfunction, due to their anti-inflammatory action” (Specification Paragraph 0008). Indeed, as evidenced by Hazarbassanov (Investigative Ophthalmology & Visual Science, 55:3684, 2014) and Maissa et al (Contact Lens & Anterior Eye 33:76-82, 2010) castor oil itself is active in the treatment of dry eye. In particular, as taught by Hazarbassanov, “topical castor-oil lubricant… led to significant improvement in symptoms such as dryness” (Results). And, as taught by Maissa et al, “castor oil eyedrops achieved a residence time of at least four hours post-instillation and produced a more stable tear film and an associated decrease in ocular symptoms over the entire 4 h follow-up period for the symptomatic patients” suffering from dry eye (Page 81, Column 2).
While it is well settled that a showing of unexpected results is generally sufficient to overcome a prima facie case of obviousness (In re Albrecht, 514 F.2d 1389 (CCPA 1975)), as recognized by the court in In re Schulze, 346 F.2d 600 (CCPA 1965), mere arguments are not sufficient to demonstrate unexpected results. Rather, unexpected results must be established by factual evidence by comparing the claimed invention with that of the closest prior art. In re Burckel, 592 F.2d 1175 (CCPA 1979). As discussed by the court in In re De Blauwe, 736 F.2d 699 (Fed. Cir. 1994), “the absence of tests comparing [Applicant’s claimed invention] with those of the closest prior art… constitute mere argument”. In the instant case, Applicant has not compared the claimed invention with that of the closest prior art (i.e., Wei et al) and provided factual evidence which establishes unexpected results of the claimed invention. To demonstrate unexpected results, Applicant should compare a SLN comprising cholesterol as the solid lipid and castor oil as the liquid lipid (as taught by Wei et al) with a NLC comprising cholesterol as the solid lipid and castor oil as the liquid lipid (as instantly claimed) in the treatment of dry eye or on biomarkers thereof. Evidence that the NLC structure provides a greater than expected result when compared to the SLN would likely be considered evidence of nonobviousness.
For all the foregoing reasons, Applicant’s arguments are not found persuasive. The rejection of claims is MAINTAINED.
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.
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 17-18, 20 and 25-26 are MAINTAINED rejected under 35 U.S.C. 103(a) as being unpatentable over Wei et al (US 2016/0074321; of record) in view of Seyfoddin et al (Drug Development and Industrial Pharmacy 39:508-519, 2013; of record) and Viladot Petit et al (US 2013/0017239; of record).
As amended, claim 17 is drawn to a method of treating or preventing a dry eye disorder (more specifically, dry eye syndrome (aka keratoconjunctivitis sicca) (claim 20)) in a subject, the method comprising administering to an eye or eyelid of the subject (more specifically, topically to the surface of the eye or eyelid (claim 18)), a composition comprising a Nanostructured Lipid Carrier (NLC) particle comprising:
(i) a solid outer shell comprising a solid lipid, wherein the solid lipid comprises cholesterol; and
(ii) a liquid core comprising a liquid lipid, wherein the liquid lipid comprises castor oil triglyceride;
wherein the NLC does not comprise or encapsulate a therapeutic agent other than the liquid lipid.
Wei et al teach “an ophthalmic composition including a… lipid nano-dispersion” (Paragraph 0007), which “refers to a dispersion system of solid lipid nanoparticle (SLN)” (Paragraph 0065), wherein “the lipid nano-dispersion includes a first lipid, a second lipid, and emulsifier; in which the first lipid exists in form of solid lipid… and the second lipid exists in form of liquid lipid” (Paragraph 0007), wherein “[p]referably, the solid lipid includes yellow Vaseline and wool fat” (Paragraph 0008), which comprises cholesterol, and “the liquid lipid includes at least one of… castor oil”, listed among seven options (Paragraph 0011), wherein the composition “can be used for prevention or treatment of dry eye syndrome without containing any active pharmaceutical agent” (Paragraph 0058), said method comprising “the step of administering to the subject an effective amount of the ophthalmic composition” (Paragraph 0040), in particular topically to the surface of the eye of said subject (see, e.g., Paragraph 0170).
However, although Wei et al state that “[t]he lipid nano-dispersion is similar to the nanostructured lipid carrier that was developed from SLN” (Paragraph 0066) and disclose “preparation of the lipid nano-dispersion” in a way which would seemingly provide an NLC having the liquid lipids enclosed in the solid lipid shell (Paragraph 0031-0035), Wei et al nevertheless state that, “[c]ompared to NLC, lipid nano-dispersion has a higher concentration of liquid lipids. Therefore, the solid lipids maybe entrapped in the liquid lipids” (Paragraph 0067).
As such, the method of treating dry eye syndrome taught by Wei et al differs from the instantly claimed method in that Wei et al teach the administration of a lipid nano-dispersion (i.e., solid lipid nanoparticle) comprising a solid lipid comprising cholesterol and a liquid lipid comprising castor oil as opposed to a nanostructured lipid carrier comprising the solid lipid cholesterol as a solid outer shell and liquid lipid castor oil as a liquid core as claimed.
Yet, as taught by Seyfoddin et al, “SLNs can be successfully converted to physically superior NLCs” (Abstract), which “are structural modifications of SLNs developed to address their insufficiencies, such as… stability problems” (Page 513, Column 1).
And, Viladot Petit et al teach “nanostructured lipid carriers (NLC)” (Abstract) wherein “[t]he solid lipid is selected, without restriction, from… sterols, cholesterol and cholesterol esters” and so on, (Paragraph 0041) and “[t]he liquid lipid is selected, without restriction, from the group formed by vegetable oils, such as… castor oil” (Paragraph 0040).
Accordingly, in further view of Seyfoddin et al and Viladot Petit et al it would have been prima facie obvious to modify the method of Wei et al by utilizing an NLC for administration as opposed to an SLN. It would have been obvious to do so to provide a physically superior delivery device having enhanced stability, as taught by Seyfoddin et al, and with a reasonable expectation of success, based on Seyfoddin et al (which teach that “SLNs can be successfully converted to physically superior NLCs”) and based on Viladot Petit et al (which generically disclose the feasibility of NLCs comprising a solid outer shell comprising cholesterol and a liquid core comprising castor oil triglyceride).
Based on all of the foregoing, claims 17-18 and 20 are rejected as prima facie obvious.
Claims 25-26 are drawn to the method of claim 17 wherein the NLC particle comprises about 1:1 of solid outer shell relative to the liquid core (claim 25), more specifically about 1:1 of cholesterol relative to castor oil (claim 26).
As taught by Wei et al, “[p]referably, based on the total volume of the ophthalmic composition, the ophthalmic composition includes 0.1% ~ 6% (w/v) of the first lipid” (Paragraph 0071) and “0.1% ~ 10% (w/v) of the second lipid” (Paragraph 0074).
And, as taught by Viladot Petit et al, “in the mixtures of lipids of the NLC the liquid lipids and solid lipids are mixed in a proportion which… [is] preferably between 50:50 and 0.1:99.9%” (Paragraph 0042).
As such, claims 25-26 are also rejected as prima facie obvious. As discussed by MPEP 2144.05, “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists” (citing In re Wertheim, 541 F.2d 257 (CCPA 1976); In re Woodruff, 919 F.2d 1575 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465 (Fed. Cir. 1997)).
Claims 21-23 are MAINTAINED rejected under 35 U.S.C. 103(a) as being unpatentable over Wei et al (US 2016/0074321; of record) in view of Seyfoddin et al (Drug Development and Industrial Pharmacy 39:508-519, 2013; of record) and Viladot Petit et al (US 2013/0017239; of record; of record) as applied to claims 17-18, 20 and 25-26 above, as evidenced by Mubofu (Sustain Chem Process 4:11, 2016; of record).
Claims 21-23 are drawn to the method of claim 17 wherein the triglyceride comprises ricinoleic acid, oleic acid and linoleic acid (claim 22), wherein ricinoleic acid is the majority fatty acid component of the NLC particle (claim 21), more specifically, wherein the triglyceride comprises at least 85% ricinoleic acid (claim 23).
As evidenced by Mubofu, castor oil “exists as a mixture of saturated and unsaturated fatty acids attached to a glycerol” wherein, “[i]n the mixture of castor oils fatty acids, ricinoleic acid accounts for about 90% of the mixture with all other components in small proportions of not more than 5%” (Page 3, Column 2), wherein the other components include oleic acid and linoleic acid (Page 4, Figure 4).
As such, claims 21-23 are also rejected as prima facie obvious.
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 §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 17-18, 20-23 and 25-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 11,779,543.
Although the claims at issue are not identical, they are not patentably distinct from each other. The ‘543 claims are similarly drawn to a method of treating/preventing an eye disorder in a subject comprising administering to said subject’s eye an NLC comprising a solid outer shell comprising cholesterol, and a liquid core comprising a liquid lipid comprising a triglyceride and “the therapeutic agent” which is understood to either include said triglyceride (claim 21) wherein the triglyceride can be castor oil (claim 4), or further entail an agent separate from said triglyceride which is castor oil (claim 21).
Claims 17-18, 20-23 and 25-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 9-21 and 24-25 of copending Application No. 18/458,828.
Although the claims at issue are not identical, they are not patentably distinct from each other. The ‘828 claims are similarly drawn to a method of treating/preventing an eye disorder in a subject comprising administering to said subject’s eye an NLC (claims 24-25) comprising a solid outer shell comprising cholesterol (claims 1-3), and a liquid core comprising a liquid lipid comprising a triglyceride containing castor oil (claims 1 and 4).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CRAIG D RICCI whose telephone number is (571) 270-5864. The examiner can normally be reached on Monday through Thursday, and every other Friday, 7:30 am - 5:00 pm ET.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany Barham can be reached on (571) 272-6175. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CRAIG D RICCI/Primary Examiner, Art Unit 1611