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 .
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 10/24/2025 is acknowledged. Claims 1-25 are pending, of which claims 6-15 and 21-25 are withdrawn from consideration as being directed to a non-elected invention. Claims 16-20 are withdrawn as being directed to non-elected species as non-biodegradable. Claims 1-5 encompass the elected invention (Group I) and species (biodegradable) and are examined herein on the merits for patentability.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1 and 3 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wall et al. (US 2019/0135741).
Wall discloses treating a disease associated with oxidative damage, comprising administering a pharmaceutical composition comprising (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) (diNACA) to a patient in need thereof. In one aspect, the disease is an eye disease or disorder. In another aspect, the disease is retinitis pigmentosa. In another aspect, the disease is antivenom, beta-thallassemia, cataract, chronic obstructive pulmonary disease, macular degeneration, contrast-induced nephropathy, asthma, lung contusion, methamphetamine-induced oxidative stress, multiple sclerosis, Parkinson's disease, platelet apoptosis, Tardive dyskinesia, Alzheimer disease, HIV-1-associated dementia, mitochondrial diseases, myocardial myopathy, neurodegenerative diseases, pulmonary fibrosis, Friedreich's ataxia (paragraph 0010).
DiNACA may be coupled to one or more soluble, biodegradable, bioacceptable polymers as drug carriers or as a prodrug. Such polymers may include: polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues, mixtures thereof, and the like. Furthermore, diNACA may be coupled one or more biodegradable polymers to achieve controlled release of the diNACA, biodegradable polymers for use with the present invention include: polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels, mixtures thereof, and the like (paragraph 0042).
Regarding the intended use of the biodegradable polymer comprising diNACA as an intraocular implant, it is noted that the recitation of the intended use does not distinguish over Wall because the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See In re Casey, 152 USPQ 235 (CCPA 1967) and In re Otto, 136 USPQ 458, 459 (CCPA 1963). See also MPEP 2111.02, directed to preamble statements limiting structure and preamble statements reciting purpose or intended use. In the instant case it is considered that the compositions are capable of treating age-related macular degeneration, are capable of intraocular (including intravitreal or intracameral) administration (paragraph 0063) and the claim language does not impart any structural features that distinguish the claimed polymer comprising diNACA from the prior art.
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 and 3-5 are rejected under 35 U.S.C. 103 as being unpatentable over Hector et al. (Orphanet Journal of Rare Diseases, 2022, 17, 23) in view of Dutta (US 2020/0054486).
Hector teaches evaluation of anticystinotic activity of novel compounds, N-acetylcysteine amide (NACA, NPI-001) and (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) (diNACA, NPI-002), compared to cysteamine, with a view to determining whether these compounds may be safe and sufficient to reduce cystine and thereby effectively treat nephropathic or ocular cystinosis.
Currently, both NACA and diNACA are in clinical trials based on their antioxidant properties. An intravitreal implant containing diNACA is under evaluation as an anticataract treatment (NPI-002 Intravitreal Implant for the Delay of Cataract Progression (ClinicalTrials.gov Identifier: NCT05026632)) (page 7).
NACA and diNACA caused no cytotoxicity. Treatment with all tested concentrations (25, 50 or 75 µM) of either NACA or diNACA at 48 or 72 h resulted in statistically significant increases in cell viability, relative to untreated control, whereas the higher concentrations (50 or 75 µM) of cysteamine achieved statistical significance at both timepoints, but not the lowest concentration (25 µM). Cystine reduction was determined as percent of control after incubation with 50 µM of NACA, diNACA or cysteamine in HCFs cell culture for 6, 24, 48 and 72 h. Rank order potency for cystine reduction over time was observed: NACA>diNACA≥cysteamine. These findings warrant further evaluation of NACA and diNACA as potential therapies for nephropathic or corneal cystinosis (page 7).
Hector does not specifically teach that the implant comprises a biodegradable polymer.
Dutta teaches a biodegradable intravitreal implant comprising an antioxidant and a biodegradable polymer that releases the antioxidant at a predetermined rate effective to sustain release of an amount of the antioxidant from the implant for a prolonged period of time after the implant is placed into the vitreous of an eye.
The biodegradable intravitreal implants according to the disclosure herein comprise an antioxidant and a biodegradable polymer. The antioxidant according to the disclosure herein is a carotenoid selected from lutein, zeaxanthin or a combination thereof. According to the disclosure herein the biodegradable polymer is selected from homopolymers of lactic acid, and copolymers of lactic acid and glycolic acid, i.e., poly(lactide-co-glycolide) or polylactide or “PLGA” polymers (paragraph 0006).
The implants may further include phospholipids (see paragraph 0018 and Examples).
The biodegradable intravitreal implants according to the disclosure herein comprises antioxidant in a range of about 30% by weight to about 70% by weight of the implant, and the biodegradable polymer in a range of about 30% by weight to about 70% by weight of the implant (paragraph 0008).
It would have been obvious to one of ordinary skill in the art at the time of the invention that an intravitreal implant comprising diNACA as taught by Hector would comprise a biodegradable polymer when the teaching of Hector is taken in view of Dutta. One would have been motivated to provide diNACA in an intravitreal implant comprising a biodegradable polymer because Dutta teaches that doing so releases the antioxidant at a predetermined rate effective to sustain release of an amount of the antioxidant from the implant for a prolonged period of time after the implant is placed into the vitreous of an eye. With regard to claims 4 and 5, Dutta teaches combinations of antioxidants may be used in the compositions. 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).
Claim(s) 1 and 3-5 are rejected under 35 U.S.C. 103 as being unpatentable over Wall et al. (US 2020/0222344) in view of Dutta (US 2020/0054486).
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.
Dutta teaches a biodegradable intravitreal implant comprising an antioxidant and a biodegradable polymer that releases the antioxidant at a predetermined rate effective to sustain release of an amount of the antioxidant from the implant for a prolonged period of time after the implant is placed into the vitreous of an eye (abstract).
Age elated macular degeneration (ARMD) is a severe problem of the eye which accounts for the loss of vision of huge number of elderly population across the globe. The disease which starts as a mild innocent problem of the eye, including occasional floaters and black dots in front of the eye gradually progresses to the loss of peripheral vision to complete loss of vision (paragraph 0002).
Antioxidants are well known to slow down the progression of the ARMD disease. There are several formulations available in the market containing single or combination of antioxidants like Alpha Tocopherol, Lutein, Zeaxanthin, Selenium, etc for oral administration for slowing down the progression of the disease. There are several drawbacks with orally administered drugs or bioactives as the drug does not reach the eye at appropriate concentrations and has either none or very poor pharmacological action in the eye when administered through oral route (paragraph 0003).
Hence, there is a need for a topical formulation of antioxidants like Lutein and/or Zeaxanthin for Intraocular or Intravitreal administration that will release the drug at a predetermined rate for an extended period of time thereby maintaining a steady concentration of antioxidants in the vitreous humor for a prolonged period of time thereby precluding the need of repeated administration and leading to better safety and efficacy, for effective management of ARMD (paragraph 0004).
The biodegradable intravitreal implants according to the disclosure herein comprise an antioxidant and a biodegradable polymer. The antioxidant according to the disclosure herein is a carotenoid selected from lutein, zeaxanthin or a combination thereof. According to the disclosure herein the biodegradable polymer is selected from homopolymers of lactic acid, and copolymers of lactic acid and glycolic acid, i.e., poly(lactide-co-glycolide) or polylactide or “PLGA” polymers (paragraph 0006).
The implants may further include phospholipids (see paragraph 0018 and Examples).
The biodegradable intravitreal implants according to the disclosure herein comprises antioxidant in a range of about 30% by weight to about 70% by weight of the implant, and the biodegradable polymer in a range of about 30% by weight to about 70% by weight of the implant (paragraph 0008).
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 Dutta. Each of Wall and Dutta are directed to provision of an antioxidant for treatment of macular degeneration. While Wall teaches that diNACA may be administered intravitreally, it is not specifically stated that intravitreal administration comprises an intravitreal implant comprising a biodegradable polymer. However, one would have been motivated to provide diNACA in an intravitreal implant comprising a biodegradable polymer because Dutta teaches providing an antioxidant in an intraveal implant releases the antioxidant at a predetermined rate effective to sustain release of an amount of the antioxidant from the implant for a prolonged period of time after the implant is placed into the vitreous of an eye, including for treatment of macular degeneration. For example, Dutta teaches intravitreal administration that will release the drug at a predetermined rate for an extended period of time thereby maintaining a steady concentration of antioxidants in the vitreous humor for a prolonged period of time provides the advantage of precluding the need of repeated administration and leading to better safety and efficacy, for effective management of ARMD.
With regard to claims 4 and 5, Dutta teaches combinations of antioxidants may be used in the compositions and that an antixodiant may be in a range of about 30% by weight to about 70% by weight of the implant. Wall teaches that the amount of the diNACA 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. Further, Wall 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).
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.
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).
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 an 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.
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).
Conclusion
No claims are allowed at this time.
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/LHS/
/Michael G. Hartley/ Supervisory Patent Examiner, Art Unit 1618