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 Claims
Claims 1-18 are pending. Applicant amended claims 3, 4, 7-12, and 14. There are no claims withdrawn and no claims canceled.
Claims 1-18 are under consideration in the instant office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 7/3/2024 and 1/22/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 3 is objected to because of the following informalities:
-In claim 3, the abbreviations/acronyms; AM80, and NEt-3IB are not spelled out.
Appropriate corrections are required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 10, and 18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for treating or preventing an eye disorder in an individual comprising administering to the individual an effective amount of a composition, does not reasonably provide enablement for “reducing the risk of having an eye disorder in an individual” using a “an effective amount of a composition comprising one or more retinoid X receptor (RXR) agonists” across all routes, dosing ranges, and plethora of diseases listed in claims 10 and 18.
Additionally, the specification does not reasonably provide enablement for particular dosage amounts, administration routes, and pharmacokinetic properties. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The claims recite, inter alia, methods of “treating or preventing or reducing the risk of having an eye disorder in an individual” using one or more retinoid X receptor (RXR) agonists over extremely broad dose, route, regimen, and disease-types.
Claim 1 recites broadly a method encompassing treatment, prevention, and reducing risk of having an eye disorder in an individual using an effective amount of a composition comprising “one or more retinoid X receptor (RXR) agonists”.
Claim 3 recites pharmaceutical compositions; “RXR agonist” which comprises 9-cis retinoic acid, oleic acid, omega-3 docosahexaenoic acid, vitamin D, bexarotene, taxerotene, honokiol, AM80, rosiglitazone, Drupanin, garcinoic acid, NEt-3IB, or a combination thereof.
Dependent claims 4-13 add very broad numeric ranges for unit does (0.1-5000 ng or mg of the RXR agonist), a wide variety of dosing intervals (from once daily to multiple times daily) and routes of administration, including an eye drop (and a microdrop), ointment or cream, and by subconjunctival injection.
Claim 10 extends the method of claim 1 to a wide spectrum of etiologically distinct ocular and systemic disorders (dry eye disease, Sjogren's Syndrome, Meibomian gland disease, unstable tear film, tear dysfunction, or an ocular surface inflammatory condition, vitamin A deficiency, chemical corneal injury, thermal corneal injury, cornea inflammation following bacterial, fungal or viral infection, corneal neovascularization, or a combination thereof; claim 18 further defines the conditions that predispose an individual to the eye disorder.
The specification provides enabling data for only a narrow subset of agonists (primarily 9-cis retinoic acid) in specific murine models of IL-17-driven eye and ex vivo cell systems. It identifies the suppressive effects of examples of RXRα agonists on IL-17 production by cultured γδ T cells, and differences in immune cells and gene expression between wild type C57BL/6 and Pinkie mice. Similar to the conjunctiva, there was an increase in IL-17 producing γδ T cells, which shows the importance of RXRα in suppressing this key inflammatory cytokine (Example 10—Examples of Effects of RXRα Agonists [0159]), but these examples do not provide established regimens for prevention or risk reduction using RXRα Agonists.
Accordingly, the claims are far broader than what is actually taught and reasonably predictable, particularly as to risk reduction of having an eye disorder across all claimed retinoid X receptor (RXR) agonists doses, routes, regimens, and disease types.
The instant specification fails to provide information that would allow the skilled artisan to practice the instant invention. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
Nature of the Invention:
The instant invention relates to immunology, ophthalmology, medicinal chemistry, and pharmaceutical formulation. It seeks to leverage RXR agonists to modulate IL-17-driven inflammation in a variety of ocular disorders, including those secondary to systemic autoimmune diseases, vitamin A deficiency, and different corneal injuries.
The field is complex and relatively unpredictable for several reasons:
Small changes in retinoid or RXR-agonist structure can have significant effects on receptor selectivity, pharmacokinetics, and toxicity at the ocular surface and systemic level (Gaunt, Christopher M et al. “The MS Remyelinating Drug Bexarotene (an RXR Agonist) Promotes Induction of Human Tregs and Suppresses Th17 Differentiation In Vitro.” Frontiers in immunology vol. 12 712241. 10 Aug. 2021).
IL-17-driven inflammation is context-dependent; suppressing IL-17 pathways may have different consequences in infectious vs. noninfectious ocular conditions, and in immune-privileged tissues like the eye (Conclusion; David S Tierney, Kenneth J Mandell, David Lacey, Joseph Tauber, David Wirta, Joseph Martel, David G. Evans; Safety, Tolerability, and Efficacy of A197, a Novel IL-17A Antagonist, in Subjects with Dry Eye Disease. Invest. Ophthalmol. Vis. Sci. 2024;65(7):2975).
The ocular surface is sensitive to irritant effects of formulations; prior art shows that even modest variations in concentration and vehicle for retinoids can affect tolerability and efficacy in dry eye patients (Maumenee, A E et al. “Topical retinoid treatment for various dry-eye disorders.” Ophthalmology vol. 96,5 (1989): 730. doi:10.1016/s0161-6420(89)32831-4).
The complex and somewhat unpredictable nature of ocular immunomodulatory therapy, especially when repurposing systemic RXR agonists or structurally diverse compounds, means that successful treatment is not a matter of routine extrapolation from in vitro IL-17 suppression.
The State of the Prior Art:
At the time of filing, the art included multiple approaches to treating dry eye and related ocular surface inflammatory conditions:
Topical retinoic acid ointments had been clinically evaluated for severe dry eye and squamous metaplasia, using specific, empirically derived concentrations and vehicles (Murphy, P T et al. “Successful use of topical retinoic acid in severe dry eye due to chronic graft-versus-host disease.” Bone marrow transplantation vol. 18,3 (1996): 641-2).
Numerous patents and publications addressed formulations and methods for treating dry eye with various agents (e.g., cyclosporin, lifitegrast, lubricant compositions), often devoting extensive disclosure to formulation, dosing and clinical data (WO 2007/087609 A2 – Formulations and methods for treating dry eye).
Immunomodulators targeting IL-17 or related pathways in ocular disease were emerging, with dedicated ophthalmic formulations and clinical safety studies (Conclusion; David S Tierney, Kenneth J Mandell, David Lacey, Joseph Tauber, David Wirta, Joseph Martel, David G. Evans; Safety, Tolerability, and Efficacy of A197, a Novel IL-17A Antagonist, in Subjects with Dry Eye Disease. Invest. Ophthalmol. Vis. Sci. 2024;65(7):2975).
Thus, at the time of filing, while the prior art demonstrated that retinoids can, with careful optimization, be used for dry eye, it does not render predictable the full breadth of RXR agonists and indications claimed here. This is because the prior art underscores the need for detailed, drug-specific and indication-specific development.
The Relative Skill of those in the Art:
The level of skill in the art is a neuro-oncologist or clinician with a Ph.D., and/or an M.D.
The Predictability or Lack thereof in the Art:
The predictive value of the described IL-17 pathway modulation for clinical outcomes across all claimed disorders and agonists is limited.
IL-17 and Th17/γδ T17 biology in ocular disease is complex; targeting IL-17 may have different effects depending on whether the disease is autoimmune (e.g., Sjorgen’s) versus infectious or mechanical (e.g., chemical burns), and outcomes can be influenced by compensatory pathways (NIH/National Eye Institute. "Dual role discovered for molecule involved in autoimmune eye disease." ScienceDaily. ScienceDaily, 26 July 2020).
Retinoid and RXR agonist pharmacology in ocular tissue is sensitive to compound lipophilicity, receptor selectivity (RXR versus RAR, and heterodimer partners), and local metabolic conversion; these parameters are not easily predicted from the limited data provided (Gaunt, Christopher M et al. “The MS Remyelinating Drug Bexarotene (an RXR Agonist) Promotes Induction of Human Tregs and Suppresses Th17 Differentiation In Vitro.” Frontiers in immunology vol. 12 712241. 10 Aug. 2021).
Prior art shows that IL-17 antagonists developed specifically for ophthalmic use required dedicated clinical trials to establish safety, tolerability, and efficacy (e.g., A197 ophthalmic solution for dry eye), underscoring that success in systemic or non-ocular models does not guarantee predictable ocular outcomes (David S Tierney, Kenneth J Mandell, David Lacey, Joseph Tauber, David Wirta, Joseph Martel, David G. Evans; Safety, Tolerability, and Efficacy of A197, a Novel IL-17A Antagonist, in Subjects with Dry Eye Disease. Invest. Ophthalmol. Vis. Sci. 2024;65(7):2975).
Given this unpredictability, in both, immune pathway modulation and ocular pharmacology, and the lack of efficacy data for all RXR agonists, it is not reasonable to assume that any and all combinations of claimed doses, routes, and regimens will achieve the full array of outcomes (treatment, prevention, and risk reduction) without extensive empirical work.
The Breadth of the Claims:
Claims 1, 10, and 18 are broad along multiple axes:
Chemical breadth: “One or more RXR agonists”, explicitly including diverse small molecules (retinoids, fatty acids, Vitamin D, thiazolidinediones, phenolic compounds, etc.) and “any analog thereof”.
Disease and indication breadth: An array of eye disorders and systemic conditions with heterogeneous etiologies, ranging from aqueous-deficient dry eye and Meibomian gland disease to corneal neovascularization and ocular manifestations of systemic autoimmune disease, GVHD, and Stevens-Johnson syndrome.
Regimen and Route of Administration scope: Numerous administration routes (eye drops, microdrops, injections, systemic routes), a wide dosing spectrum (multiple orders of magnitude), and broad frequency statements (once-daily, multiple times per day), with limited compound-specific guidance.
In contrast, the enabling disclosure is essentially focused on:
One principal agonist (9-cis retinoic acid) in
Specific murine models with reduced RXRα signaling (Pinkie strain) and desiccating stress, plus ex vivo cultures of murine γδ T cells and monocytes.
Prior art reinforces that even within retinoid therapy for dry eye, narrower claims tied to particular compounds, concentrations, vehicles, and clinical contexts were supported by detailed examples and clinical data, unlike the broad, multi-agonist, multi-indication claims here.
Accordingly, the breadth of the claims is not commensurate with the scope of the enabling disclosure. The breadth of these claims far exceeds the limited examples and data actually provided.
As such, the breadth of the claims is great.
The Amount of Direction or Guidance Presented:
Although the specification contains detailed mechanistic and pathway analyses (e.g., scRNA-seq, IL-17 signaling network maps, Nanostring panels, ATAC-seq and motif analysis) demonstrating that 9-cis retinoic acid reduces IL-17 inducers and IL-17A/F production in murine γδ T cells and monocytes, the document offers little practical guidance on how to translate these mechanistic observations into safe, effective, clinically applicable dosing regimens across the broad spectrum of claimed RXR agonists, routes, and diseases.
The specification provides a sweeping list of possible doses, expressed as numerous integer values from 0.1 to 5000 ng or μg and from 0.14 to 0.57 mg/kg, without anchoring these enumerated values to specific clinical scenarios, agonists, or patient populations.
The routes of administration (eyedrop, microdrop, ointment, cream, subconjunctival injection) are recited generically, with formulation discussion largely imported from standard pharmaceutical dispensations rather than data-driven guidance specific to each RXR agonist.
For non-retinoid agonists such as bexarotene, rosiglitazone, honokiol, drupanin, garcinoic acid and others, the specification does not provide ocular pharmacokinetic data, local tolerability data, or examples of in vivo dosing in eye disease models.
Existing prior art on dry eye therapy demonstrates that formulation and delivery of small molecules to the ocular surface is nontrivial and requires specific optimization for each drug, including vehicle selection, particle size and preservative choice. For instance, dry eye formulations using cyclosporin or other agents had to be carefully optimized to increase tear film stability and minimize irritation, and those formulations cannot simply be translated to unrelated RXR agonists (WO2007087609A2 – Formulations and methods for treating dry eye).
Thus, while the specification teaches generally that 9-cis retinoic acid suppress IL-17A/F production in certain murine systems, it does not provide sufficient guidance to practice the full scope of claims 1, 10, and 18 across the diverse agonists and disease states recited without extensive, individualized experimentation.
The Presence or Absence of Working Examples and Quantity of Experimentation:
The specification contains working examples primarily in murine models of dry eye driven by an RXRα loss-of-function mutation (Pinkie strain) and in ex vivo or invitro assays involving γδ T cells and monocytes.
Figures 1-3 and related description demonstrate that Pinkie mice with reduced RXRα signaling develop dry eye, with increased IL-17-producing γδ T cells and related cytokines.
Figures 4A-4D and 12 show that administration of 9-cis retinoic acid in vitro or ex vivo reduces IL-17A/F production by γδ T cells and modulates expression of IL-17 inducers in monocytes.
Figures 6A-6E and 11illustrate bone marrow chimera experiments and the role of IL-17 neutralization in modulating dry eye signs in mice, again in the context of specific murine genetic backgrounds and desiccating stress.
However, the specification does not provide:
In vivo therapeutic examples showing topical or subconjunctival administration of 9-cis retinoic acid or any other RXR agonist directly to the eye in a dry eye animal model; or
Clinical data in human subjects with dry eye disease, Sjorgen’s syndrome, GVHD or the other claimed conditions.
By contrast, prior art on retinoid treatment of dry eye shows actual clinical use of specific concentrations of topical retinoic acid ointments in defined patient populations (e.g., 0.01% and 0.1% all-trans retinoic acid for severe dry eye with squamous metaplasia), which underscores that working examples are typically needed to support therapeutic method claims of the breadth recited in the instant application (Murphy, P T et al. “Successful use of topical retinoic acid in severe dry eye due to chronic graft-versus-host disease.” Bone marrow transplantation vol. 18,3 (1996): 641-2.).
Moreover, prior art dry eye methods using other agents (e.g., cyclosporine formulations) demonstrate that multiple detailed clinical examples, including formulation specifics and dosing regimens, are commonly provided to enable such claims.
Given that the working examples in the instant application are confined to a narrow murine context and largely mechanistic, they do not reasonably enable the full clinical breadth of claim 1, 10, and 18.
To enable the full claim scope of claims 1, 10, and 18, a skilled artisan would have to engage in extensive, iterative, unduly burdensome clinical experimentation to implement “one or more RXR agonists” across all claimed eye disorders, routes, vehicles, and dosing regimens that are very large. To implement the claimed methods for each RXR agonist listed (and their analogs) in each of the diverse indicated disorders and routes, the skilled artisan would have to conduct extensive, case-by-case experimentation to determine:
Safe and effective ocular doses for each agonist in humans;
Appropriate formulation (e.g., solubilization, stability, preservative system) for each chemotype;
Specific dosing regimens and treatment durations for each underlying disease state; and
Whether IL-17-modulation and clinical benefit generalize beyond the particular murine Pinkie strain and the wild type in dry eye model.
This level of trial-and-error analysis, across many agonists and disease etiologies, goes well beyond routine optimization and constitutes undue experimentation.
Note that lack of a working example, is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art. See MPEP 2164. Genentech, Inc. v. Novo Nordisk, 108 F.3d at 1366, states that "a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion" and "[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable". Therefore, in view of the Wands factors, e.g., the amount of direction or guidance provided, absence of working examples, and the predictability of the art discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation in order to practice invention based on the details provided and scope of invention defined in claims 1, 10 and 18.
Consequently, claims 1, 10 and 18 are rejected for lacking scope of enablement.
Claim Rejections - 35 USC § 112(b)
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 1-18 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.
Regarding claim 1, the phrase "effective amount" at line 2 renders the claim indefinite, because PHOSITA could not determine specific values for the amount based on the disclosure. See MPEP § 2173.05(c)(III). For example, see above enablement rejection regarding guidance provided and unpredictability in the art. With respect to dependent claim 9, although this claim recites a laundry list of possible “effective doses,” there is no guidance in the specification as to which dose(s) would be appropriate for which eye disorder. Consequently, what is an “effective amount” in the context of the claimed method is ambiguous and cannot be ascertained reasonably by PHOSITA.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-4 and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Alam, Jehan et al. (“Retinoid Regulation of Ocular Surface Innate Inflammation.” International journal of molecular sciences vol. 22,3 1092. 22 Jan. 2021) herein referred to as Alam.
Regarding claims 1-2, Alam teaches method for treating/preventing eye disorder by administering retinoid X receptor (RXR) agonist (Abstract). Alam teaches the role of RXRα signaling involvement in ocular surface inflammation, maintaining ocular surface homeostasis and dry eye disease and suggests therapeutic modulation of RXR signaling (2.3. Effects of Retinoic Acid on Innate Immune Cells, Paragraph 4, lines 1-3). Alam specifically teaches RXRα biology in conjunctival immune cells (Abstract and Fig. 4 (A, D)).
Regarding claims 3-4, Alam teaches that RXR agonist includes 9-cis retinoic acid (Abstract; lines 4-5, Fig. 4 (C) and 2.3. Effects of Retinoic Acid on Innate Immune Cells, Paragraph 1, lines 5-7). While Alam does not explicitly teach therapeutic composition that is administered to one or both eyes of the individual, ophthalmic delivery is inherently contemplated for ocular disease treatment. Moreover, the ordinary skilled artisan would clearly envisage administration to one or both eyes, because ophthalmic delivery necessarily is understood to be administration to the eye or eyes and humans only have two eyes.
Regarding claim 10, while Alam does not explicitly teach entire disease list recited in claim 10, it discusses dry eye disease and ocular inflammatory conditions (2.3. Effects of Retinoic Acid on Innate Immune Cells, Paragraph 1, lines 5-7 and Paragraph 5, lines 2-3) that are recited in the alternate.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Applicant Claims
2. Determining the scope and contents of the prior art.
3. Ascertaining the differences between the prior art and the claims at issue, and 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 1-18 are rejected under 35 U.S.C. 103(a) as being unpatentable over Alam, Jehan et al. (“Retinoid Regulation of Ocular Surface Innate Inflammation.” International journal of molecular sciences vol. 22,3 1092. 22 Jan. 2021) in view of US 2005/0287115 A1 to Coroneo (“TREATMENT OF OCULAR LESIONS” hereinafter 'Coroneo' publication: 2005/0287115A1) and further in view of US 2005/0271705 A1 to Hughes et al. ("Retinoid-containing sustained release intraocular drug delivery system and related methods", filed Apr. 29, 2005).
Regarding claims 5-8, Alam teaches the method of claims 1-3 as detailed above. However, Alam does not explicitly teach administration forms/routes of therapeutic composition.
Coroneo teaches a method for treating (abstract) or preventing or reducing the risk of having an eye disorder (abstract) in an individual comprising administering to the individual an effective amount of a composition comprising one or more retinoid X receptor (RXR) agonists (paragraphs [0013]; [0025]; [0036]). Coroneo teaches the method of claim 1, wherein the RXR agonist is an RXRα agonist (para [0037] 9-cis-retinoic acid). Coroneo also teaches the method of claim 1 or 2, wherein the RXR agonist comprises 9-cis retinoic acid (para [0037], 9-cis- retinoic acid), oleic acid, omega-3 docosahexaenoic acid, vitamin D, bexarotene, taxerotene, honokiol, AM80, rosiglitazone, Drupanin, garcinoic acid, NEt-3IB, or a combination thereof.
Coroneo further teaches different administration forms/routes of therapeutic composition wherein retinoid may be administered to the eye in an eyedrop composition ([0032] and claim 6). Coroneo further teaches wherein retinoid may be administered by intralesional injection ([0035] and claim 7).
It would have been obvious to a person having ordinary skill in the art at the time the invention was filed to formulate the therapeutic composition of Alam and Coroneo as a microdrop, an ointment or cream, and as a subconjunctival injectable formulation; thus, arriving at the claimed invention. One skilled in the art would be motivated to do so, with a reasonable expectation of success, because formulating the composition as a microdrop, an ointment or cream, and as a subconjunctival injectable formulation provides the benefits of good dissolution rate as well as optimize the therapeutic effects, as taught by Coroneo.
Regarding therapeutic composition amounts of components in the formulation of RXR agonist in claim 9, it is noted that, while Alam and Coroneo do not specifically teach full dosage range identical to those instantly claimed, the optimum amounts of the presently claimed active agents and excipients would have been a matter well within the insight of one of ordinary skill in the art. Such a determination would have been made in accordance with a variety of factors, such as the route of administration, pharmacological considerations, such as the activity, efficacy, pharmacokinetics and toxicology profiles of the combination regimen, as well as the age, weight, sex, diet and medical condition of the patient, and the severity of the condition. Thus, the determination of the optimum or workable amounts given the guidance of the prior art would have been generally prima facie obvious to the ordinary skilled artisan. Please see MPEP 2144.05 [R-2] (II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (“[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation."). Accordingly, the particular amounts claimed do not impart patentability to the claims, absent a showing of the criticality of the particular amounts claimed.
Regarding claims 11-13, Alam teaches the method of claims 1-3 as detailed above. However, Alam does not explicitly teach the frequency of administration of therapeutic composition comprising one or more retinoid X receptor (RXR) agonists.
Coroneo teaches different frequencies of administration of therapeutic composition comprising one or more retinoid X receptor (RXR) agonists wherein retinoid may be administered by instilling eyedrops into the eye over a treatment period until the particular condition being treated resolves. Preferably, the retinoid is administered sequentially on every second day during treatment [0030]. Coroneo teaches that treatment duration is carried out until the disease condition has resolved, although shorter or longer treatment durations may be required depending on the severity of the lesion. [0041].
It would have been obvious to a person having ordinary skill in the art at the time the invention was filed to optimize the frequency of dosage or therapeutic composition of Alam and Coroneo to once per day to several times per day; thus, arriving at the claimed invention. One skilled in the art would be motivated to do so, with a reasonable expectation of success, because optimizing the frequency of dosage or therapeutic composition can maximize the benefit/risk profile or provide the desired therapeutic effect while minimizing toxicity or adverse effects.
Regarding claims 14-16, Alam teaches the method of claims 1 as detailed above. However, Alam and Coroneo do not explicitly teach composition that is administered with another therapy and whether that therapy includes any compositions recited in claims 15-16.
Hughes teaches many retinoid drugs that are formulated for oral delivery, for example, RAR agonists such as isotretinoin (Accutane), RXR agonists such as bexarotene (Targretin) and RAR, RXR dual agonists such as acitretin (Soriatane) [0009]. Hughes further teaches in addition to the retinoid component included in the intraocular drug delivery systems disclosed, the intraocular systems may also include one or more additional ophthalmically acceptable therapeutic agents. For example, the systems may include one or more antihistamines, one or more antibiotics, one or more beta blockers, one or more steroids [0220]. Examples of antibiotics include without limitation, cefazolin, cephradine, cefaclor, cephapirin, ceftizoxime, cefoperazone, cefotetan, cefutoxime, cefotaxime, cefadroxil, ceftazidime, cephalexin, cephalothin, cefamandole, cefoxitin, cefonicid, ceforanide, ceftriaxone, cefadroxil, cephradine, cefuroxime, cyclosporine, ampicillin, amoxicillin, cyclacillin, ampicillin, penicillin G, penicillin V potassium, piperacillin, oxacillin, bacampicillin, cloxacillin, ticarcillin, azlocillin, carbenicillin, methicillin, nafcillin, erythromycin, tetracycline, doxycycline, minocycline [0223], thereby meeting the limitations of claims 14-16.
It would have been obvious to a person having ordinary skill in the art at the time the invention was filed to combine therapeutic composition of Alam and Coroneo with Hughes one or more additional ophthalmically acceptable therapeutic agents; thus, arriving at the claimed invention. One skilled in the art would be motivated to do so, with a reasonable expectation of success, because the therapeutic agents or substances used to treat a medical condition of the eye are typically ophthalmically acceptable, and are provided in a form that does not cause adverse reactions when the system is placed in an eye, as taught by Hughes [0099].
Regarding claims 17-18, Alam and Coroneo teach the method of claims 1 as detailed above. However, Alam and Coroneo do not explicitly teach wherein the individual has a condition that predisposes the individual to the eye disorder and whether the condition comprises any one of the conditions recited in claims 17-18.
Hughes discloses many present systems that may also be configured to release the retinoid or additional therapeutic agents to prevent various exemplified diseases or conditions [0248]. Hughes exemplifies corneal diseases, dry eye syndromes [0105] and ocular inflammatory and immune disorders, ocular vascular malfunctions, Corneal Graft Rejection, Neovascular Glaucoma and the like [0258].
It would have been obvious to a person having ordinary skill in the art at the time the invention was filed to combine the teachings of Alam and Coroneo with the teachings of Hughes; thus, arriving at the claimed invention. One skilled in the art would be motivated to do so, with a reasonable expectation of success, because it is known in the art that many underlying conditions make an individual prone to eye disorders. Many eye disorders are “downstream” effects of other health problems for example; autoimmune and inflammatory conditions such as lupus or Sjögren’s syndrome can cause inflammation in the eye, leading to dry eye syndrome or other inflammatory eye diseases.
Conclusion
Claims 1-18 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAHAR INAM whose telephone number is (571)272-0821. The examiner can normally be reached 7:30 am-5:00 pm EST.
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, James H Alstrum-Acevedo can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. 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.
/SAHAR INAM/
Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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