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 .
Acknowledgement of Receipt
Applicant’s Response, filed 4/9/2026, in reply to the Office Action mailed 12/9/2025, is acknowledged and has been entered. Claim 1 has been amended. Claims 1-25 are pending, of which claims 6-25 are withdrawn from consideration at this time as being drawn to a non-elected invention and/or species. Claims 1-5 encompass the elected invention and species and are examined herein on the merits for patentability.
Response to Arguments
Any rejection not reiterated herein has been withdrawn as being overcome by claim amendment. The Hector reference has been withdrawn as prior art in view of the Declaration of Inventor Wall. New grounds for rejection are set forth hereinbelow. The Examiner’s response to Applicant’s arguments is incorporated below.
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.
Claim(s) 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Wall et al. (US 2020/0222344) in view of Hughes (US 2005/0244470).
Wall teaches treatment of age-related macular degeneration, glaucoma, or diabetic retinopathy in a human that comprises administering to the human a therapeutically effective amount of N-acetylcysteine amide (NACA) or (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) (diNACA) sufficient to treat or reduce the symptoms of the age-related macular degeneration, glaucoma, or diabetic retinopathy.
NACA or diNACA are administered orally, intravenously, intramuscularly, enterally, intraocularly, subretinally, intravitreally (claim 3).
NACA or diNACA are administered in daily doses of about 0.5 to 150 mg/Kg (claim 4).
Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions (paragraph 0044). Antioxidants include, but are not limited to, α-tocopherol, ascorbic acid, Mn(III)tetrakis (4-benzoic acid) porphyrin, α-lipoic acid, and n-acetylcysteine (paragraph 0035).
Formulations of the present invention include those suitable for oral, nasal, topical, transdermal, buccal, sublingual, intramuscular, intraperotineal, intraocular, intravitreal, subretinal, and/or other routes of parenteral administration. The specific route of administration will depend, inter alia, on the specific cell to be targeted. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect (paragraph 0046).
The embodiments of the invention can, for example, be administered by injection, intraocularly, intravitreally, subretinal, intravenously, intraarterially, subdermally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, directly to a diseased organ by catheter, topically, or in an ophthalmic preparation, with a dosage ranging from about 0.001 to about 100 mg/kg of body weight, or according to the requirements of the particular drug and more preferably from 0.5-10 mg/kg of body weight. It is understood that when a compound is delivered directly to the eye, considerations such as body weight have less bearing on the dose (paragraph 0080).
Wall does not specifically teach wherein diNACA is provided as an intravitreal implant comprising a biodegradable polymer.
Hughes teaches biocompatible intraocular implants include a tyrosine kinase inhibitor and a biodegradable polymer that is effective to facilitate release of the tyrosine kinase inhibitor into an eye for an extended period of time. The therapeutic agents of the implants may be associated with a biodegradable polymer matrix, such as a matrix that is substantially free of a polyvinyl alcohol. The implants may be placed in an eye to treat or reduce the occurrence of one or more ocular conditions.
Delivery of drugs to the retina, vitreous and uveal tract is typically achieved by high systemic dosing, intra-ocular injections or other heroic measures. Penetration of systemically administered drugs into the retina is severely restricted by the blood-retinal barriers (BRB) for most compounds. Although intraocular injection, such as intravitreal injections, resolves some constraints posed by the BRB and significantly reduces the risk of systemic toxicity, intraocular injection techniques may result in retinal detachment, physical damage to the lens, exogenous endophthalmitis, and also may result in high pulsed concentrations of drug at the lens and other intraocular tissues (paragraph 0003).
The present invention provides new drug delivery systems, and methods of making and using such systems, for extended or sustained drug release into an eye, for example, to achieve one or more desired therapeutic effects. The drug delivery systems are in the form of implants or implant elements that may be placed in an eye. The present systems and methods advantageously provide for extended release times of one or more therapeutic agents. Thus, the patient in whose eye the implant has been placed receives a therapeutic amount of an agent for a long or extended time period without requiring additional administrations of the agent. For example, the patient has a substantially consistent level of therapeutically active agent available for consistent treatment of the eye over a relatively long period of time, for example, on the order of at least about one week, such as between about one and about six months or even for more than one year after receiving an implant. Such extended release times facilitate obtaining successful treatment results. The implants allow for prolonged delivery of a therapeutic agent while reducing invasive procedures and reducing high transient concentrations associated with pulsed dosing.
The pharmaceutical compositions may be in the form of a sterile injectable preparation (paragraph 0083).
Intraocular implants in accordance with the disclosure herein comprise a therapeutic component and a drug release sustaining component associated with the therapeutic component. The implants may be solid, semisolid, or viscoelastic. In accordance with the present invention, the therapeutic component comprises, consists essentially of, or consists of, a tyrosine kinase inhibitor (TKI), for example, an agent or compound that inhibits or reduces the activity of tyrosine kinase. The TKI may also be understood to be a small molecule TKI. The drug release sustaining component is associated with the therapeutic component to sustain release of an amount of the TKI into an eye in which the implant is placed. TKIs may be released from the implant by diffusion, erosion, dissolution or osmosis. The drug release sustaining component may comprise one or more biodegradable polymers or one or more non-biodegradable polymers. Examples of biodegradalbe polymers of the present implants may include poly-lactide-co-glycolide (PLGA and PLA), polyesters, poly(ortho ester), poly(phosphazine), poly(phosphate ester), polycaprolactone, natural polymers such as gelatin or collagen, or polymeric blends. The amount of the TKI is released into the eye for a period of time greater than about one week after the implant is placed in the eye and is effective in reducing or treating an ocular condition (paragraph 0009).
In one embodiment, intraocular implants comprise a therapeutic component that comprises a TKI, and a polymeric outer layer covering the therapeutic component. The polymeric outer layer includes one or more orifices or openings or holes that are effective to allow a liquid to pass into the implant, and to allow the TKI to pass out of the implant. The therapeutic component is provided in a core or interior portion of the implant, and the polymeric outer layer covers or coats the core. The polymeric outer layer may include one or more non-biodegradable portions. The implant can provide an extended release of the TKI for more than about two months, and for more than about one year, and even for more than about five or about ten years (paragraph 0012).
The implants may be placed in an ocular region to treat a variety of ocular conditions, such as treating, preventing, or reducing at least one symptom associated with non-exudative age related macular degeneration, exudative age related macular degeneration, etc. (paragraph 0016).
The TKI of the implant is preferably from about 10% to 90% by weight of the implant. More preferably, the TKI is from about 20% to about 80% by weight of the implant. In a preferred embodiment, the TKI comprises about 40% by weight of the implant (e.g., 30%-50%). In another embodiment, the TKI comprises about 60% by weight of the implant (paragraph 0075).
In addition to the TKI(s) included in the intraocular implants disclosed herein, the intraocular implants may also include one or more additional ophthalmically acceptable therapeutic agents. For example, the implant may include one or more antihistamines, one or more antibiotics, one or more beta blockers, one or more steroids, one or more antineoplastic agents, one or more immunosuppressive agents, one or more antiviral agents, one or more antioxidant agents, and mixtures thereof (paragraph 0102). Examples of antioxidant agents include ascorbate, alpha-tocopherol, mannitol, reduced glutathione…N-acetylcysteine, etc. (paragraph 0111).
Rods implants are taught and are manufactured by pelletizing the polymer/drug melt using a 9 gauge polytetrafluoroethylene (PTFE) tubing, loading the pellet into the barrel and extruding the material at the specified core extrusion temperature into filaments. The filaments are then cut into about 1 mg size implants or drug delivery systems. The rods have dimensions of about 2 mm x 0.72 mm diameter (paragraph 0168). In addition, fiber diameter will generally be in the range of about 0.05 to 3 mm and the fiber length will generally be in the range of about 0.5-10 mm. Spheres may be in the range of about 0.5 µm to 4 mm in diameter, with comparable volumes for other shaped particles (paragraph 0099).
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide diNACA in an intravitreal implant comprising a biodegradable polymer when the teaching of Wall is taken in view of Hughes. Each of Wall and Hughes are directed to provision of a therapeutic agent to the eye for treatment of macular degeneration. While Wall teaches that diNACA may be administered intravitreally, it is not specifically stated that intravitreal administration comprises a rod-shaped intravitreal implant comprising a biodegradable polymer. However, one would have been motivated to provide diNACA in an intravitreal implant comprising a biodegradable polymer because Hughes teaches that intravitreal implant delivery systems advantageously provide for extended release times of one or more therapeutic agents, thus the patient in whose eye the implant has been placed receives a therapeutic amount of an agent for a long or extended time period without requiring additional administrations of the agent. For example, Hughes teaches that implants allow for prolonged delivery of a therapeutic agent while reducing invasive procedures and reducing high transient concentrations associated with pulsed dosing, including teaching rod-shaped implants. Further, Wall teaches sterile injection, as the means to delivery therapeutic agent to the eye.
With regard to claims 4 and 5, Hughes teaches various one or more additional ophthalmically acceptable therapeutic agents may be used in the compositions including antioxidants among others. Further, Hughes teaches an active agent in a range of about 10% by weight to about 90% by weight of the implant, and Wall teaches that the amount of the compound in a carrier is one that produces a therapeutic effect, accordingly it would have been obvious to one of ordinary skill in the art to adjust the amount of antioxidant, diNACA, as a means of routine optimization in order to achieve therapeutic effect. Wall further teaches in an ophthalmic preparation, with a dosage ranging from about 0.001 to about 100 mg/kg of body weight and it is understood that when a compound is delivered directly to the eye, considerations such as body weight have less bearing on the dose. Furthermore, differences in concentration or temperature will generally not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; or In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
Response to arguments
Applicant argues that claim 1 has been amended to clarify that the implant is rod-shaped. Applicant asserts that nothing in the art of Wall teaches that the implant is a rod. Applicant asserts that the combination of Wall and Hughes fails to render the present invention obvious because there is no motivation to combine the references. Specifically, Hughes teaches an implant that requires the presence of a tyrosine kinase inhibitor, not NACA. Applicant contends that Hughes fails to motivate its combination with Wall as these are distinct molecules.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that Hughes readily teaches rod-shaped implants as a suitable vehicle for intravitreal administration. With regard to the argument that there is no motivation to combine the references as Hughes teaches an implant that requires the presence of a tyrosine kinase inhibitor, not NACA, it is respectfully submitted that each of Wall and Hughes are directed to provision of a therapeutic agent to the eye for treatment of macular degeneration. Hughes is relied upon for teaching a suitable vehicle for delivery of intravitreal administration, as well as the benefit of intravitreal implant delivery systems as advantageously providing for extended release times of one or more therapeutic agents, thus the patient in whose eye the implant has been placed receives a therapeutic amount of an agent for a long or extended time period without requiring additional administrations of the agent. Accordingly, one of ordinary skill desiring to provide intravitreal administration of NACA, as in Wall, would have been motivated to achieve the benefit of extended release and reduced administration, as taught by the implant in Hughes. Applicant’s arguments have been fully considered but the rejection is maintained.
Conclusion
No claims are allowed at this time.
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.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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