DETAILED ACTION
Status of the Claims
Claims 39, 44-56, and 58-62 are pending in the instant application and are being examined on the merits in the instant application.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.
Priority
The U.S. effective filing date has been determined to be 11/10/2015, the filing date of the priority document GB 1519811.2.
Claim Rejections - 35 USC § 112(a)
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim 60 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a New Matter Rejection.
Scope of the Claimed Invention:
Applicant claims a composition for preparing an ocular implant, consisting essentially of: 99 to 60% (w/w) of a first polymeric biodegradable composition comprising a monomer selected from the group consisting of polyalkylene glycol diacrylate and polyalkylene glycol dimethacrylate, wherein the first polymeric composition has a molecular weight of about 200 to about 20,000 Dalton and wherein the first polymeric composition is photopolymerizable; a second biodegradable polymer that is not photopolymerizable; a photoinitiator; a therapeutic agent; and optionally, one or more of a non-aqueous solvent, a pore-forming agent, and a co-initiator; and wherein the composition is a homogeneous mixture (instant claim 39). And claim 16 recites “The composition of claim 39, wherein the composition is injectable through a needle of 27 gauge or a smaller-diameter needle.”
Disclosure of the Instant Application:
Applicant’s arguments state that: “New claim 60, depending from claim 39, recites, "wherein the composition is injectable through a needle of 27 gauge or smaller," and can find support in Example 3 of the specification.” (p. 14, 3rd paragraph, lines 1-3). Example 3 points to Figure 6 and states that: “In addition to drug release, it is also important to demonstrate the injectability of these in situ forming implant gels, as these are designed to be injected in the eye using hypodermic needles or microneedles following short-term application of UV light. Figure 6 represents the WoS for each ISPcl formulation that was calculated from the resulting force-distance plots of Texture-Analysis. The WoS data indicates that the PLGA/PEGDA formulations for both PLGA 50/50 and PLGA 75/25 require different forces to expel them from the syringe with 27G needle. In general the PLGA75/25 formulations are more easily expelled compared to the PLGA50/50 formulations with a WoS of 43.23 N.mm calculated for the PLGA50/50-PEGDA700 formulation, with 22.55 N.mm calculated for the PLGA75/25-PEGDA700 formulation. It would be expected that the highest molecular weight of PEGDA would result in the greatest resistance to expulsion. This trend is followed when considering the PLGA75/25 formulations but not with the PLGA50/50. The greatest WoS was seen with the PLGA 50/50-PEGDA258 formulation, 48.24 N.mm, which is significantly greater than the other PLGA5050 formulations (p < 0.0001 ). Therefore, the implant forming gels can be injected and the forces for injections vary by changing the composition/concentration of the polymers within the ISPcl formulation.” (p. 25, 2nd paragraph).
Discussion:
The examiner finds no support for “wherein the composition is injectable through a needle of 27 gauge or a smaller-diameter needle” (claim 60), and while the specification does disclose that “the PLGA/PEGDA formulations for both PLGA 50/50 and PLGA 75/25 require different forces to expel them from the syringe with 27G needle”, the base claim 39 are not limited to PLGA 50/50 or PLGA 75/25. Therefore, the support for “wherein the composition is injectable through a needle of 27 gauge” is not fully supported for the claimed subject matter. The Specification clearly indicates that higher molecular weight increase resistance to expulsion (“It would be expected that the highest molecular weight of PEGDA would result in the greatest resistance to expulsion.”) and the examples only include “Poly(ethylene glycol) diacrylate (PEGDA) molecular weight (Mw) 258, 575 and 700 Da” (p. 22, line 5), which is PEGDA258, PEGDA575, and PEGDA700. Instant claim 39 is generic to “polyalkylene glycol diacrylate and polyalkylene glycol dimethacrylate, wherein the first polymeric composition has a molecular weight of about 200 to about 20,000 Dalton”. Therefore, the scope of claim 39 “wherein the composition is injectable through a needle of 27 gauge” is not fully supported. Therefore, the claim 60 is rejected as failing to comply with the written description requirement as the claim contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor, at the time the application was filed, had possession of the claimed invention.
Claim Rejections - 35 USC § 112(b)
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 39, 44-56, and 58-62 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.
Claim 39 recites the limitation "the composition is a homogenous mixture" in line 13. There is insufficient antecedent basis for this limitation in the claim. Particularly it is unclear what “the composition” is required to be “a homogenous mixture.” Appropriate clarification is required. Dependent claims 44-52, 60 and 61 inherit and do nothing to clarify the above discussed issue, and are therefore rejected for the same reasoning.
Claim 44 recites the limitation "the first polymeric composition" in line 1. There is insufficient antecedent basis for this limitation in the claim. Appropriate clarification is required.
Claim 53 recites the limitation "the composition is a homogenous mixture" in line 10. There is insufficient antecedent basis for this limitation in the claim. Particularly it is unclear what “the composition” is required to be “injectable through a needle of 27 gauge or a smaller-diameter needle.” Appropriate clarification is required. Dependent claims 54-56, 58, 59 and 62 inherit and do nothing to clarify the above discussed issue, and are therefore rejected for the same reasoning.
Claim 60 recites the limitation "the composition" in line 1. There is insufficient antecedent basis for this limitation in the claim. Particularly it is unclear what “the composition” is required to be “a homogenous mixture.” Appropriate clarification is required.
Claim 60 is further rejected as being indefinite because the claim recites “wherein the composition is injectable through a needle of 72 gauge or a smaller-diameter needle.” Where it is unclear what exactly the limitation “a smaller-diameter needle.” Because gauge is not a measure of diameter, and needles have different diameters including at least an inner and an outer diameter, as well as different diameters if the needle is not a cylinder-shape (e.g. broader at base, narrower at the tip). Appropriate clarification is required.
Claim 62 recites the limitation "the first polymeric composition" in line 1. There is insufficient antecedent basis for this limitation in the claim. Appropriate clarification is required.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 39, 44-56 and 58-62 are rejected under 35 U.S.C. 103 as being unpatentable over DADEY ‘604 (US 2006/0210604; published August, 2010) in view of DADEY ‘305 (US 2011/0171305; published July, 2011); KLIMAN (US 2009/0196903; published August, 2009); Mieler et al. (“Thermo responsive Hydrogels as New Ocular Drug Delivery Platform to the Posterior Segment of the Eye," 2008, Transactions of the American Ophthalmological Society, Vol. 106, pp. 206-214); SCHWARTZ (US 6,149,931; published November, 2000); and Baroli (“Physicochemical Characterization of Photopolymerizable PLGA Blends,” 2006, In: Fisher, J.P. (eds) Tissue Engineering, Advances in Experimental Medicine and Biology, vol 585, Chapter 13, pp. 183-196).
Applicants Claims
Applicant claims a composition for preparing an ocular implant, consisting essentially of: 99 to 60% (w/w) of a first polymeric biodegradable composition comprising a monomer selected from the group consisting of polyalkylene glycol diacrylate and polyalkylene glycol dimethacrylate, wherein the first polymeric composition has a molecular weight of about 200 to about 20,000 Dalton and wherein the first polymeric composition is photopolymerizable; a second biodegradable polymer that is not photopolymerizable; a photoinitiator; a therapeutic agent; and optionally, one or more of a non-aqueous solvent, a pore-forming agent, and a co-initiator; and wherein the composition is a homogeneous mixture (instant claim 39), and an ocular implant comprising the same (claim 57).
Determination of the scope
and content of the prior art (MPEP 2141.01)
DADEY ‘604 teaches ocular delivery of polymeric delivery formulations (title, see whole document), and particularly that: “a flowable composition suitable for use as a controlled release implant. The flowable composition can be administered into the ocular region of a mammal. The composition includes: (a) a biodegradable, biocompatible thermoplastic polymer that is at least substantially insoluble in aqueous medium, water or body fluid; (b) a biological agent, a metabolite thereof, a biological a gently acceptable salt thereof, or a prodrug thereof; and (c) a biocompatible organic liquid, at standard temperature and pressure, in which the thermoplastic polymer is soluble. The present invention also provides methods of medical treatment that include administering the flowable composition into the ocular region of a mammal.” (abstract).
DADEY ‘604 teaches that: “The present invention provides a flowable composition suitable for use as a controlled release implant, the composition includes: (a) a biodegradable, biocompatible thermoplastic polymer that is at least substantially insoluble in aqueous medium, water or body fluid; (b) a biological agent, a metabolite thereof, a biological agent acceptable salt thereof, or a prodrug thereof; and (c) a biocompatible organic liquid, at standard temperature and pressure, in which the thermoplastic polymer is soluble; wherein the composition is suitable for ocular delivery.” ([0013])(instant claim 39, “A composition for preparing an ocular implant”). And that: “The present invention also provides an implant that includes: (a) a biodegradable, biocompatible thermoplastic polymer that is at least substantially insoluble in aqueous medium, water or body fluid; (b) a biological agent, a metabolite thereof, a biological agent acceptable salt thereof, or a prodrug thereof; and (c) a biocompatible organic liquid at standard temperature and pressure, in which the thermoplastic polymer is soluble; wherein the implant is located in the ocular region of a mammal and the implant has a solid or gelatinous microporous matrix, the matrix being a core surrounded by a skin and wherein the implant is surrounded by body tissue.” ([0017])(instant claim 53, “An ocular implant”).
DADEY ‘604 teaches that: “The biological agent(s) can be suitable for local delivery in the eye. Alternatively, the biological agent(s) can be suitable for systemic delivery via the eye.” ([0047]). DADEY ‘604 teaches that: “The flowable composition described herein can be locally administered, via the ocular region, to treat one or more eye diseases or disorders. Suitable eye diseases or disorders include, e.g., […], Age Related Macular Degeneration (AMD), […].” ([0164]).
DADEY ‘604 teaches that: “In particular, the monomers used to make the biocompatible thermoplastic branched polymers of the present invention will produce polymers or copolymers that are biocompatible and biodegradable. Examples of biocompatible, biodegradable polymers suitable for use as the biocompatible thermoplastic branched polymers of the present invention include polyesters, polylactides, polyglycolides, […] and copolymers, terpolymers, or combinations or mixtures of the above materials.” ([0078]), and the organic solvent includes polyethylene glycols ([0048], [0094]). The biocompatible organic liquid solvent being present in an amount of about 50 wt% to about 70 wt.% (claim 35). DADEY ‘604 teaches the inclusion of a pore forming additive ([0175]).
DADEY ‘604 teaches intraocular injection – “Injections were performed directly into the eye (intravitreal injection), […].” ([0232]-[0233]), and teaches “Several ATRIGEL® formulations were found to be acceptable for ocular implantation over a short time period using either route of administration, specifically, these included formulations containing PEG300, mPEG350, PEG400 and NMP. Therefore, a long-term irritation study was conducted with ATRIGEL® formulations containing PEG300, mPEG350 and NMP utilizing both routes of administration. The results of the long-term study show that polymer degradation occurs as expected and that no prolonged irritation is observed. Thus, ATRIGEL® formulations containing PEG300, mPEG350 and NMP can be considered acceptable vehicles for intravitreal or subconjunctival implantation and subsequent drug delivery.” ([0236]). And that: “Due to the sensitivity of the tissues in the eye, only
ATRIGEL® vehicles with the most biocompatible solvents will be used in the initial studies. The initial solvents studied will consist of polyethylene glycol 300 (PEG300), PEG400, polyethylene glycol monomethylether 350 (mPEG350), n-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), and glycerol triacetate (triacetin). In addition, a known ocular irritant, benzethonium chloride (BEC) will be evaluated to observe a positive response. A single polymer, 50/50 poly(lactide-co-glycolide) (PLGH) with an inherent viscosity of 0.18 dL/g will be used throughout the studies, a constant injection volume of 50 μL and a 25-gauge 5/s inch needle will also be used.” ([0240])(instant claims 39, 45, 46 & 53, “second biodegradable polymer – PLGA). DADEY ‘604 teaches the amount of the PLGA ranges from 15% in Examples – “The first in-vivo rabbit study was completed on Jun. 19, 2003 and it evaluated the intravitreal route of injection with 6 ATRIGEL® vehicle formulations.” ([0241], Table Group A-F).
DADEY ‘604 teaches that: “The biologically active substance of the composition and the polymer of the invention may form a homogeneous matrix, or the biologically active substance may be encapsulated in some way within the polymer.” ([0182]).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of DADEY ‘604 is that DADEY ‘604 does not expressly teach the inclusion of polyethylene glycol di(meth)acrylate, a photoinitiator, or the anti-VEGF agents aflibercept, ranibizumab, bevacizumab.
DADEY ‘305 teaches dehydrated hydrogel inclusion complex of bioactive agent with flowable drug delivery system (title, see whole document), and particularly that: “The formulation includes a dehydrated inclusion complex of the bioactive agent within a hydrogel, wherein the hydrogel can comprise a polymerized polyalkyleneglycolyl diacrylate, and, optionally, polyalkyleneglycolyl monoacrylates, including methacrylates.” (abstract).
DADEY ‘305 teaches that: “In order to sustain or prolong the release of the bioactive agent, e.g., protein, over medically useful periods of time, such as weeks or months, the inclusion complex of the agent in the multidimensional polymer matrix is contained within a mass of a second type of polymer adapted to provide for controlled release. The second type of polymer may be a biodegradable polymer, a biodegradable polyester, or a biodegradable poly(lactide-glycolide) copolymer, as described above.” ([0039]). DADEY ‘305 teaches that: “This process continues until the depot is substantially completely dissolved and all the bioactive agent is released. It is understood that such depots can be adapted to persist for various lengths of time within the body, such as about 30 days, about 60 days, or about 3 months, 4 months, or 6 months.” ([0004])(instant claims 53-56 & 58 – release period and degradation period).
DADEY ‘305 teaches the bioactive is a protein such as bevacizumab (AVASTIN)([0018])(instant claims 48, 49 & 52).
DADEY ‘305 teaches that: “It is understood that when a PEG diacrylate monomer undergoes polymerization, polyacrylate chains are formed, but any covalently connected PEG polyacrylate molecule can, and is believed to, include more than just two polyacrylate chains, as polymerizing acrylate groups can join any growing chain and are not restricted to always at each step of acrylate incorporation joining the same chain. Therefore, it is believed that the polymerized PEG diacrylate or the copolymerized PEG diacrylate/PEG monoacrylate materials of the invention possess highly three-dimensional structures wherein many individual polyacrylate backbones are interconnected via the PEG chains.” ([0026]). And that: “The polymerization or copolymerization of the PEG diacrylate or diacrylate plus monoacrylate, termed herein the "polymerization reaction," can be carried out by any suitable means known in the art, but preferably the polymerization reaction is initiated by the use of ultraviolet (UV) light. Preferably an initiator adapted for activation by UV light is included at an appropriate concentration in the aqueous medium, for example at a concentration of about 0.1 wt%. An example of an initiator suitable for use is l-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propan-1-one (Irgacure 2959). Illumination of the aqueous solution of the monomers and preferably the initiator, for example with UV light of a wavelength of about 365 nm, results in the polymerization of the PEG acrylate monomers and the formation of a hydrogel.” [emphasis added]([0044]). And further that: “It is understood that a person of ordinary skill in the art can select a UV activated initiator and an illumination wavelength suitable to give a desired degree of polymerization without undue experimentation. It is also within the skill of the ordinary practitioner to select a monomer concentration and an initiator concentration to give polymerized products of the desired molecular weights, which depend upon the degree of polymerization of the acrylate moieties.” ([0045]).
DADEY ‘305 teaches that: “When the polyoxyalkyleneglycol group is a polyethyleneglycol group, bearing a second acrylate ester at its distal end (termed a "polyoxyalkyleneglycolyl diacrylate"), the molecular weight of the polyethyleneglycol moiety can range between about 500 Da and about 10,000 […].” ([0019]). And that: “For example, description of the molecular weight of the polyethyleneglycol moiety ranging between about 500 Da and about 10,000 Da should be considered to have specifically disclosed subranges, such as between about 750 Da and about 2,000 Da, between about 1000 Da and about 1500 Da, etc., as well as individual numbers within that range, such as about 700 Da, about 2500 Da, about 5000 Da, etc.” ([0057]). And further claims “The formulation of claim 4 wherein the polyalkyleneglycolyl diacrylate has a molecular weight of about 500 Da to about 10,000 Da.” (claim 23)(instant claims 39, 44, 53, 62).
Baroli teaches that: “While testing if PLGA microspheres could be introduced into a photopolymerizable model macro-monomer, it was found that microspheres dissolved completely in the macro-monomer. It was very interesting to note that a hydrophobic polymer (PLGA) could dissolve into a hydrophilic macro-monomer (PEGDM) without the need of organic solvents and then producing transparent fluids. Therefore, the possibility of using PLGA as a biodegradable hydrophobic excipient for formulating photopolymerizable systems was investigated.” (p. 183, 2nd paragraph)(instant claim 61, the second biodegradable polymer is dissolved in the first polymeric biodegradable and photopolymerizable composition). The examiner notes that “transparent fluids” implies “a homogenous mixture” (MPEP §2144.01)(instant claims 39 & 53 – “wherein the composition is a homogenous mixture). And further that: “Consequently, a major formulative study where several different macro-monomers and PLGAs are used to produce and characterize photopolymerized networks has being undertaken. This contribution aims to describe the physico-chemical properties of one of these systems, which is composed of poly(D,L-lactide-co-glycolide) (PLGA) and the liquid macro-monomer poly(ethylene glycol) dimethacrylate (PEGDM).” [emphasis added](p. 183, §13.1, paragraphs 2-3). And further that: “These characterizations showed that PEGDM-PLGA formulations are stable, viscous but easily injectable fluids that can be rapidly photopolymerized under mild conditions, which are all appealing properties that allows these systems to be further developed for drug delivery and/or tissue engineering applications.” (p. 184, 3rd paragraph).
Baroli teaches that: “PEGDM-PLGA blends, would have a whole supply of properties necessary for being also easily injectable, which is one of the most important properties for all the in-vivo applications (e.g.; in-situ formation of scaffold for tissue regeneration or drug delivery implants), when photopolymerization in situ is carried out through minimal invasive surgery.” (p. 193, 3rd paragraph, lines 11-15).
Baroli concludes that: “The results of this study showed that PLGA could be blended with PEGDM without the use of organic solvents to produce viscous, easy injectable fluids that might be easily photopolymerized using a blue-light and a camphorquinone/amine photoinitiator system. The results presented and those anticipated in here showed that these formulations have some appealing features that might be useful in the formulative development of photopolymerized matrices to be used in tissue engineering and drug delivery.” (pp. 194-195, §13.5).
Regarding the limitation “wherein the first polymeric biodegradable and photopolymerizable composition was photopolymerized to form a cross-linked gel encapsulating the second biodegradable polymer and the therapeutic agent.” (instant claim 59), it would have been prima facie obvious to combine the PEGDA/PEGMA with the PLGA (Baroli et al. teaching the PEGDM as a solvent for PLGA) and to include the therapeutic agent for controlled/extended release. The resulting crosslinked polymer network is reasonably interpreted as encapsulating the PLGA and the therapeutic agent (instant claim 59).
Baroli teaches that: “Photopolymerizable systems have been proposed as good candidates for drug delivery and tissue engineering for their ability to be produced in vivo via minimally invasive surgery upon light or UV exposure.” (p. 183, §13.1, lines 1-3).
KLIMAN teaches “Implantable drug delivery devices, and kits and methods incorporating them are described. The devices may, for example, be configured for implantation into an ocular region of a subject.” (title, abstract, see whole document).
KLIMAN teaches that: “the drug delivery devices may provide for long term (e.g., weeks, months, or years) drug regimens without the need for repeated invasive surgical procedures.” ([0050]). And that: “Biodegradable polymers may also be used to configure devices having device bodies that erode over extended periods of time, e.g., over at least about six months, or over at least about one year or more. In this instance, the duration of drug release from the reservoirs may be shorter than the time it takes for the device body to degrade. In order to achieve this extended period of degradation, any number of biodegradable polymers or subtypes, combinations, blending, or crosslinking thereof may be used.” ([0080])(instant claims 53-56 & 58 - release period and degradation period).
KLIMAN teaches the drugs for delivery include ranibizumab, bevacizumab, aflibercept, and dexamethasone, among others ([0082], claims 38-40, 43, 124-126 & 129)(instant claims 48-52).
KLIMAN teaches that: “In some variations, the methods may comprise implanting the drug delivery device into the vitreous cavity of the subject through an implantation site under a conjunctiva and sealing the implantation site after implantation by pushing or closing the conjunctiva over the implantation site. Implantation may be done subconjunctivally or sub-Tenon's layer, or in any intraocular, periocular, or orbital location. In some cases, the drug delivery devices may be implanted using a surgical incision. In other cases, the drug delivery devices may be implanted through a 20 gauge or smaller cannula. For example, the drug delivery devices may be implanted through a 21 gauge, a 22 gauge, a 23 gauge, a 25 gauge, or a 30 gauge or even smaller cannula.” ([0133])(instant claim 60).
Mieler et al. teaches thermoresponsive hydrogels for ocular drug delivery to the posterior segment of the eye including poly(N-isopropylacrylamide) crosslinked with poly(ethylene glycol) diacrylate (see whole document). Kang et al. teaches that “Vascular endothelial growth factor (VEGF) has been identified as a key regulator of angiogenesis. It can act as an endothelial cell mitogen and increase vascular permeability along with angiogenesis. Elevated VEGF level has been correlated with several ocular diseases, such as age-related macular degeneration and diabetic retinopathy. On the basis of these findings, in the past several years, considerable progress has been made in the treatment of the wet form of age-related macular degeneration and diabetic retinopathy by using anti-VEGF therapy. Several clinical trials employing ranibizumab, including ANCHOR and MARINA, have demonstrated the success of anti-VEGF therapy." And that "Although intravitreal anti-VEGF therapy is a very promising treatment, the major drawback is that the treatment must be repeated every 4 to 6 weeks. This is not a desirable method of delivery for several reasons: patient discomfort; the need for repetitive injections with inherent complications, including endophthalmitis, retinal tear and detachment, intraocular hemorrhage, and cataract formation; and bolus administration of the agent. Currently, there is no alternative method for delivery of the anti-VEGF agent into the eye; hence, there is a great need and desire to develop a relatively noninvasive delivery method that is more effective and longer lasting than the current clinical regimen." And further that "Since the development of hydrogels in 1960, they have been of great interest to biomaterial scientists and tissue engineers. Hydrogels are polymers that have the ability to swell in water or aqueous solvent system, and they hold the solvents in a swollen cross-linked gel system for delivery. Through manipulation of permeation and diffusion characteristics, they can retain hydrophobic and hydrophilic agents, small molecules, and macromolecules. Depending on the specific structure, they can be nondegradable or degradable in their application. Numerous advantages make hydrogels an attractive platform. The aqueous environment of hydrogels can protect cells and fragile drugs (such as peptides, proteins, oligonucleotides, and DNA). They serve as a good means of transport of nutrients to cells and products from cells. They can be modified with cell adhesion ligands and can change physical state (liquid to solid) in response to pH or temperature changes. Most important, they are highly biocompatible.” (p. 206, §Introduction, paragraphs 1-3).
Mieler et al. further teaches that “The pore size of the hydrogels can be modified by the amount of PEG-DA added to the system. PNIP AAm-PEG-DA hydrogels showed a significant improvement in mechanical properties. The main objective of our work is to demonstrate that PNIP AAm-PEG-DA hydrogels can be utilized to encapsulate and release protein for ocular delivery to the posterior segment.” (p. 207, lines 3-6). And further that “Acrylates are used as end groups because they undergo very rapid photopolymerization.” (p. 208, lines 3-4).
Mieler et al. further teaches that “To examine the thermoresponsive hydrogel’s ability to encapsulate and release protein, the effect of cross-link density on the protein release rate was investigated. [ ... ] Two different fluorescently labeled proteins, BSA (mol wt= 66 kDa) and IgG (mol wt= 150 kDa), were used for the study. The rationale for using BSA and IgG is that their sizes are similar to ranibizumab and bevacizumab (Avastin), respectively, which is the key anticipated application of this drug delivery system.” [ emphasis added](p. 209, §Protein Release Studies, lines 1-2 & 6-8). And that “Lower cross-link density hydrogels released protein faster compared to the higher cross-link density hydrogels. In contrast, the more highly cross-linked hydrogels yielded smaller pore size and longer release times. However, when the pore size was smaller, the hydro gel became stiffer in composition, making it more difficult to inject through small-gauge (e.g., 27- to 30-gauge) needles. The inability to inject through small-gauge needles is an important design constraint, as the goal is to develop a minimally invasive delivery system to the target sites, such as the vitreous cavity or juxtascleral region. Through multiple trials of cross-link density and the ability to inject through small gauge needles, it was identified that ~8 μM PEG-DA is an optimal ratio.” (paragraph bridging pp. 209-210).
SCHWARTZ teaches methods directed at treating retinal breaks with a nontoxic polymer (see whole document) and teaches intravitreal injection (i.e. injection into the vitreous fluid of the eye) throughout (see, e.g., col. 6, lines 60-65). SCHWARTZ teaches "The invention provides methods for closing a retinal break in a mammal, comprising applying to the retinal surface over and around the retinal break a non-toxic polymer formulation comprising at least one polymer precursor, and transforming the polymer formulation into a gel-like coat. In a preferred embodiment, the polymer formulation comprises a photochemically reactive polymer precursor species that can be transformed from a liquid to gel form by exposure to light. Another preferred composition includes a mixture of two mutually reactive polymer precursors." (col. 2, lines 48-58).
SCHWARTZ teaches that "The polymer precursor is usually present in the polymer formulation at a concentration in a range of about 0.01 % to about 90%." (col. 4, lines 35-37)(instant claims 39 and 53, the percentage of the first biodegradable and photopolymerizable composition (e.g. PEGDA) is in the range of 99-60 wt. %). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. (MPEP §2144.05-1).
SCHWARTZ further teaches that "Preferably the polymer precursors of the invention comprise reactive termini to allow for photopolymerization, such as, for example, free radical polymerizable termini. Examples of such reactive termini include acrylates and methacrylates, with acrylates being more preferred. Preferably the polymer precursor is a PEG diacrylate or tetracrylate." ( col. 5, lines 35-41), and degradable regions relative to that of the central water-soluble domain, including polyesters such as PLA and PGA(col. 5, line 42 to col. 6, line 43) (instant claim 45). SCHWARTZ teaches that "The hydrolytic susceptibility of some of the ester linkages is in the following order: glycolidyl>lactoyl>E-caprolactyl." (col. 5, lines 55-57). SCHWARTZ further teaches "the biodegradable polymer formulation can also comprise reagents to facilitate the photopolymerization process, such as at least one photoinitiator […]." ( col. 7, lines 1-5)(instant 39, "a photoinitiator").
SCHWARTZ teaches that "Polymers that display a physicochemical response to stimuli have been explored as potential drug-delivery systems. Stimuli studied to date include chemical substances and changes in temperature, pH and electric field. Homopolymers or copolymers of N-isopropylacrylamide and poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide)(known as poloxomers) are typical examples of thermosensitive polymers, but their use in drug delivery is problematic because they are toxic and nonbiodegradable. Biodegradable polymers used for drug delivery to date have mostly been in the form of injectable microspheres or implant systems, which require complicated fabrication processes using organic solvents. Such systems have the disadvantage that the use of organic solvents can cause denaturation when protein drugs are to be encapsulated. Furthermore, the solid form requires surgical insertion, which often results in tissue irritation and damage. The methods of the invention involve the synthesis of a thermosensitive, biodegradable hydrogel consisting of polymer precursor blocks of poly(ethylene oxide) and poly(L-lactic acid). Aqueous solutions of these polymer precursors exhibit temperature-dependent reversible gel-sol transitions"(col. 9, line 10-33).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce an ocular implant for drug delivery using a photopolymerizable blend of PLGA and PEG-di(meth)acrylate, as suggested by DADEY ‘604, DADEY ‘305, KLIMAN and Baroli, for controlled and prolonged drug delivery of pharmaceuticals with application in ophthalmology such as ranibizumab, bevacizumab, aflibercept, and/or dexamethasone, as suggested by DADEY ‘604, DADEY ‘305, KLIMAN, in order to avoid repeated invasive surgical procedures, as suggested by KLIMAN; and Mieler et al. teaching “Ocular Drug Delivery Platform to the Posterior Segment of the Eye” makes clear that that “Acrylates are used as end groups because they undergo very rapid photopolymerization.” (p. 208, lines 3-4), the PEGDA-PLGA being a biodegradable alternative to the non-biodegradable N-isopropylacrylamide-PEGDA taught by Mieler et al., as suggested by SCHWARTZ in order to reduce toxicity and avoid the use of organic solvent associated with pure polyesters (e.g. PLGA), the range of the polymer precursor is usually present in the polymer formulation at a concentration in a range of about 0.01 % to about 90%, as suggested by SCHWART (col. 4, lines 35-37). Particularly, it would have been prima facie obvious to substitute the PEG solvent utilized in DADEY ‘604 with PEG-di(meth)acrylate, as suggested by DADEY ‘305 and SCHWARTZ both teaching drug delivery using PEG-di(meth)acrylate reacted gels, and particularly that Baroli teaches that Baroli teaches that: “While testing if PLGA microspheres could be introduced into a photopolymerizable model macro-monomer, it was found that microspheres dissolved completely in the macro-monomer. It was very interesting to note that a hydrophobic polymer (PLGA) could dissolve into a hydrophilic macro-monomer (PEGDM) without the need of organic solvents and then producing transparent fluids. Therefore, the possibility of using PLGA as a biodegradable hydrophobic excipient for formulating photopolymerizable systems was investigated.” (p. 183, 2nd paragraph), and Baroli concludes that: “The results of this study showed that PLGA could be blended with PEGDM without the use of organic solvents to produce viscous, easy injectable fluids that might be easily photopolymerized using a blue-light and a camphorquinone/amine photoinitiator system. The results presented and those anticipated in here showed that these formulations have some appealing features that might be useful in the formulative development of photopolymerized matrices to be used in tissue engineering and drug delivery.” (pp. 194-195, §13.5). A prima face case of obviousness based upon a substitution rationale requires (1) a finding of fact that the prior art contained a product which differed from the claimed product by the substitution of some components with other components; (2) a finding of fact that the substituted components and their functions were known in the art; (3) a finding that one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable; and (4) whatever additional findings based upon the Graham factual inquiries may be necessary, in view of the case under consideration, to explain a conclusion of obviousness (MPEP § 2143-B). In the instant case (1) DADEY ‘604 includes PEG as a solvent for PLGA, and sustained drug delivery using the same, and (2) the substituted components and their functions were known in the art, particularly both DADEY ‘305 and SCHWARTZ teach sustained drug delivery using PEG-di(meth)acrylate reacted gels; (3) one of ordinary skill would have recognized that the PEG-di(meth)acrylate could have been substituted with the PEG solvent used in DADEY ‘604, predictably dissolving the PLGA as Baroli clearly teaches this as the same; and (4) PLGA and related polymers (PLA, PGA) are FDA approved and well-known for controlled sustained drug delivery therefore obvious to select for the same, and PEG-di(meth)acrylate reacted gels are also known for sustained drug delivery and therefore would have been prima facie obvious to select for the same.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because both PLGA and PEG-di(meth)acrylate, were known in the prior art for prolonged delivery of drug for ophthalmology such as ranibizumab, bevacizumab, aflibercept, and/or dexamethasone, and it would have required no more than an ordinary level of skill in the art to produce an implant from the same. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
Response to Arguments:
Applicant's arguments filed 06/15/2026 have been fully considered but they are not persuasive.
Applicant argues that: “Ganchegui is not merely a generic PDGDA/PLGA composition. It is a carefully formed aqueous, emulsion-derived system that uses a high aqueous content in which drug-loaded PLGA micro/nano spheres are dispersed in a PEGDA-containing formulation. Applicants previously identified Ganchegui's unambiguous teaching that, "the total solid mass of all its components should be between 10 and 30% of the total volume of the formulation. Thus, compositions preserving a constant aqueous content of 70 to 90%, preferably 80%, are obtained." See, paragraph [0061] of Ganchegui. The expressly taught % solids and % aqueous content of Ganchegui are mathematically incompatible with the PEGDA amounts as claimed. That is, one cannot merely increase PEGDA to 60% as claimed without decreasing the amounts of other components in the system of Ganchegui, including the aqueous component. Such a high amount of water is not an incidental impurity or optional carrier; it materially affects the composition's structure, the PLGA sphere architecture, the polymer concentration, and the claimed w/w percentage. The Office Action's response to this line of argument hinged on the use of "comprising" in the claim language, points to the specification at p. 14 §PEGDA describing hydrogels; p. 18 describing one embodiment of making the ocular implant using an aqueous medium, and p. 19 describing that the aqueous medium "is a combination of water and phosphate buffered saline (PBS)" to assert that the specification allegedly describes using water, and then interprets the claimed 99-60% (w/w) of a first polymeric biodegradable and photopolymerizable composition as "relative to the claimed components (i.e., relative to the amount of the first and second polymers taken with the photoinitiator and the therapeutic agent)." The Office Action makes the final assertion that the claimed amount of the first polymeric biodegradable and photopolymerizable composition were routine experimentation because "simply modifying" the amount of one constituent (e.g., PEGDA) would not be considered a basis for patentability as "PEGDA was known for the very same utility", and "general conditions" for producing a PEGDA/PLGA/photoinitator/therapeutic agent compositions "would have been known to those having ordinary skill in the art" (sic) and would be considered "routine optimization".” (paragraph bridging pp. 7-8). Applicant further argues that: “First, the amended claims now recite "consisting essentially of," and therefore cannot include additional material that materially affects the basic and novel characteristics of the claimed composition or ocular implant. See, MPEP §211 l.03(III). Ganchegui separately teaches both (i) an aqueous process for making PLGA spheres and (ii) a final PEGDA/sphere structure that include embedded cells. This formulation also preserves 70-90% aqueous content, preferably 80%. See, for example, Ganchegui’s Example 1 at paragraphs [0083] and [0092] -[0094], and in paragraphs [[0001], [0024], [0037], [0061], and Abstract. Thus, even if the emulsion water used to manufacture the spheres is not carried forward as such, Ganchegui still teaches a final aqueous PEGDA/sphere/cell formulation that is materially different from the amended claims as the final formulation contains cells and has an aqueous content of at least 70%.” (paragraph bridging pp. 8-9). And that: “Second, the Office Action's interpretation of the specification describing using water focuses on a single embodiment. However, the specification does not require aqueous medium in all embodiments.” (p. 9, 2nd paragraph). Lastly, the Office Action has not addressed that arriving at the amended claims would require at least three departures from Ganchegui: first, changing Ganchegui 's final annular formulation from a high-aqueous-content PEGDA/sphere formulation to an essentially non-aqueous formulation; second, replacing Ganchegui's pre-formed PLGA spheres with dissolved PLGA, and third, removing Ganchegui 's cells from the final formulation.
In response the examiner understands that an ocular implant that includes cells would not read on the instant claims, and therefore the rejection over GANCHEGUI is withdrawn.
Applicant’s arguments with respect to claim(s) GANCHEGUI have been considered but are moot because the new ground of rejection does not rely on GANCHEGUI, as applied in the prior rejection, of record for any teaching or matter specifically challenged in the argument.
Applicant further argues that: “Dadey's system is a multi-part formulation of a dehydrated inclusion complex in a hydrogel combined with a biodegradable polymer and organic solvent, and its method dries the hydrogel/inclusion complex before dispersing it in the polymer/solvent system, not the claimed homogenous composition/implant consisting essentially of the recited components.” (p. 12, 1st paragraph). And that: “Kliman teaches implantable ocular drug delivery devices containing reservoirs and long-term delivery over weeks, months, or years. See, for example, Kliman at paragraphs [0007] and [0050]. Those teachings may relate generally to long-term ocular drug delivery, but they do not teach the claimed homogenous PEGDA/biodegradable polymer/therapeutic-agent system, do not address the “consisting essentially of” limitation, and do not provide a reason to replace Ganchegui's final aqueous PEGDA/sphere formulation with a low-water homogeneous PEGDA/PLGA mixture. Kliman supplies, at most, a general motivation for sustained ocular delivery; it does not supply the specific claimed formulation missing from Ganchegui.” (p. 12, 2nd paragraph). And further that: “The Office Action relies on Mieler for thermoresponsive hydrogels for posterior segment ocular delivery, PEGDA crosslinking, and release of model proteins similar in size to ranibizumab and bevacizumab. See, Office Action at pages 13-16. But Mieler concerns PNIPAAm-PEGDA thermoresponsive hydrogels, not a composition consisting essentially of PEGDA, a non-photopolymerizable biodegradable polymer such as PLGA, a therapeutic agent, and optional non-aqueous additives. Mieler also teaches that lower crosslink density releases protein faster, while higher crosslink density creates smaller pores and longer release times, but can make the hydrogel more difficult to inject through small-gauge needles. See, for example, Mieler at page 209. Thus, Mieler does not establish that the claimed PEGDA/PLGA compositions would be predictably injectable or would have the claimed structural properties; if anything, it confirms that injectability and release are formulation-dependent and cannot be readily predicted.” (paragraph bridging pp. 12-13).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant further argues that: “Schwartz for a broad polymer precursor concentration range of about 0.01 % to about 90%, PEG diacrylate/tetracrylate precursors, photoinitiators, and biodegradable segments. See, Office Action at pages 16-18. But a broad concentration range in a different retinal-break polymer system does not provide a reason to modify Ganchegui's aqueous PLGA-sphere formulation into the claimed homogenous composition/implant consisting essentially of the listed components. Schwartz's broad concentration range is not tied to Ganchegui 's aqueous PLGA-sphere annular formulation, and the Office Action does not explain why Schwartz would motivate moving Ganchegui from 10% PEGDA in PBS to a 60-99% PEGDA low-water composition, and does not motivate a skilled artisan to modify Ganchegui.” (p. 13, 2nd paragraph). And that: “Baroli does not cure the deficiencies of Ganchegui either. The Office Action relies on Baroli for describing that PLGA microspheres dissolved in PEGDM to form transparent fluids and discusses PLGA/PEGDM formulations that might be developed for drug delivery or tissue engineering. The Office Action relies on that "transparent fluids" disclosure to infer a homogenous mixture. See, Office Action at pages 19-21. But Baroli's cited transparent-fluid teaching is a PLGA/PEGDM physical-chemistry observation, not the claimed ocular composition/implant. Baroli does not disclose Ganchegui's aqueous sphere system, does not teach that Ganchegui 's water can be removed without destroying Ganchegui's functionality, and does not provide a reason to combine a dissolved PLGA/PEG macromer system with Ganchegui's drug-loaded PLGA sphere architecture. The Office Action's use of Baroli effectively requires selecting Ganchegui as the primary ocular reference, discarding Ganchegui 's water and PLGA spheres, importing Baroli's dissolved PLGA/PEGDM concept, then further adding the remaining claimed components and functional properties from other references. Even if Baroli teaches dissolved PLGA in PEGDM, applying Baroli to Ganchegui would require abandoning Ganchegui 's aqueous sphere-based architecture, not merely optimizing it.” (p. 13, 3rd paragraph).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
None of those references, alone or in combination, teaches or suggests the amended claims' composition/implant consisting essentially of the listed components, optional non-aqueous additives, and a homogenous mixture. Furthermore, the proposed combination of references requires a multi-step reconstruction to arrive at the claimed composition and ocular implant. The Office Action begins with Ganchegui's aqueous PEGDA/sphere annular formulation, disregards Ganchegui 's preferred 70-90% aqueous content and Example l's 80% final aqueous sample, replaces Ganchegui 's pre-formed PLGA spheres with dissolved PLGA based on Baroli, relies on Schwartz for a broad polymer precursor range, and relies on Kliman, Dadey, or Mieler for ocular-drug and sustained-release context. The Office Action does not identify a teaching in any reference that would have led a skilled artisan to make those changes to Ganchegui while preserving the function Ganchegui attributes to the PLGA spheres and high-aqueous annular formulation. Nor has the Office Action articulated a persuasive reason why a person of ordinary skill would remove Ganchegui 's required aqueous phase and PLGA sphere structure, when doing so would defeat the structure and operation that Ganchegui teaches.” (paragraph bridging pp. 13-14).
Applicant’s arguments with respect to claim(s) GANCHEGUI have been considered but are moot because the new ground of rejection does not rely on GANCHEGUI, as applied in the prior rejection, of record for any teaching or matter specifically challenged in the argument.
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 39, 44-56, and 58-62 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Application Nos. 17/414,959 (claims 1, 4, 5, 12, 13; hereafter ‘959) and 18/000,937 (claims 1-12, 14, and 15; hereafter ‘937) in view of DADEY ‘604 (US 2010/0215604; published August, 2010); DADEY ‘305 (US 2011/0171305; published July, 2011); KLIMAN (US 2009/0196903; published August, 2009); Mieler et al. (“Thermo responsive Hydrogels as New Ocular Drug Delivery Platform to the Posterior Segment of the Eye," 2008, Transactions of the American Ophthalmological Society, Vol. 106, pp. 206-214); SCHWARTZ (US 6,149,931; published November, 2000); and Baroli (“Physicochemical Characterization of Photopolymerizable PLGA Blends,” In: Fisher, J.P. (eds) Tissue Engineering, Advances in Experimental Medicine and Biology, vol 585, Chapter 13, pp. 183-196).
The instant claims are discussed above.
Copending ‘959 claim 1 recites an ocular implant comprising: (a) at least 20 to 50 % w/w of a therapeutic agent; (b) 40 to 60% w/w of a crosslinked polymer matrix; (c) and 0.1 to 10% w/w of a biodegradable polymer selected from the group consisting of poly(lactide-co-glycolide) (PLGA)), […]; wherein the implant further comprises a single coat of about 10% to about 20% polycaprolactone (PCL) having a thickness of about 20μm to about 25μm; wherein the implant is configured to have a diameter of about 0.1 mm to about 0.5 mm and a length of about 2 mm; and wherein the implant maintains a zero-order release over 180 days (instant claim 1).
Copending ‘937 claim 1 recites an ocular composition comprising: (a) at least 0.1 % w /w of a therapeutic agent; (b) 5 to 95% w/w of a photopolymerizable composition comprising 3 to 70% w/w of one or more compounds of formula I: [see claim][…], (c) 0.1 to 40% w/w of a biodegradable polymer selected from the group consisting of lactide/glycolide copolymer (including poly(lactide-co-glycolide) (PLGA[…], and (d) a photoinitiator. ‘937 claim 3 recites “wherein the compound of formula I is poly (ethylene glycol) methacrylate (PEGMA).” and “poly (ethylene glycol) diacrylate (PEGDA).” (claim 6; claim 11, item c).
The difference between the instantly rejected claims and the claims of copending ‘958 is that the claim of copending ‘958 do not expressly claim the inclusion of aflibercept, ranibizumab, or bevacizumab (instant claims 48-52), or the release/degradation period (claims 53-56 & 58).
The difference between the instantly rejected claims and the claims of copending ‘959 is that the claim of copending ‘959 do not expressly claim the inclusion of aflibercept, ranibizumab, or bevacizumab (instant claims 48-52), or the release/degradation period (claims 53-56 & 58).
The difference between the instantly rejected claims and the claims of copending ‘937 is that the claim of copending ‘937 do not expressly claim the inclusion of aflibercept, ranibizumab, or bevacizumab (instant claims 48-52), or the release/degradation period (claims 53-56 & 58).
DADEY ‘604 teaches ocular delivery of polymeric delivery formulations, as discussed above and incorporated herein by reference.
DADEY ‘305 teaches dehydrated hydrogel inclusion complex of bioactive agent with flowable drug delivery system, as discussed above and incorporated herein by reference.
KLIMAN teaches implantable drug delivery devices for long term delivery (weeks, months, years), as discussed above and incorporated herein by reference.
Baroli teaches that photopolymerizable systems have been proposed as good candidates for drug delivery, as discussed above and incorporated herein by reference.
Mieler et al. teaches thermoresponsive hydrogels for ocular drug delivery to the posterior segment of the eye. as discussed above and incorporated herein by reference.
SCHWARTZ teaches methods directed at treating retinal breaks with a nontoxic polymer, as discussed above and incorporated herein by reference.
It would have been prima facie obvious before the effective filing date of the claimed invention that the instantly rejected claims are an obvious variant of the claims of copending claims because the copending claims each include the same constituent ingredients for an ocular implant, where the prior art clearly teaches prolong delivery minimizes need for repeated invasive procedures (e.g. implantation in the eye), and each of aflibercept, ranibizumab, or bevacizumab were known ocular drugs (anti-VEGF agents for treatment of AMD). The skilled artisan would have been motivated to modify the claims of copending claims and produce the instantly rejected claim because sustained delivery of aflibercept, ranibizumab, or bevacizumab by an ocular implant would have minimized patient discomfort by minimizing implantation procedures. Furthermore, the skilled artisan would have had a reasonable expectation of success in producing the invention of the instantly rejected claims because it would have required no more than an ordinary level of skill in the art to produce an ocular implant per the claims of ‘959 and/or ‘937.
This is a provisional obviousness-type double patenting rejection.
Claims 39, 44-56, and 58-62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims of U.S. Patent No. 12,642,761 (claims 1, 6-9, 10 and 11; hereafter ‘761) in view of DADEY ‘604 (US 2010/0215604; published August, 2010); DADEY ‘305 (US 2011/0171305; published July, 2011); KLIMAN (US 2009/0196903; published August, 2009); Mieler et al. (“Thermo responsive Hydrogels as New Ocular Drug Delivery Platform to the Posterior Segment of the Eye," 2008, Transactions of the American Ophthalmological Society, Vol. 106, pp. 206-214); SCHWARTZ (US 6,149,931; published November, 2000); and Baroli (“Physicochemical Characterization of Photopolymerizable PLGA Blends,” In: Fisher, J.P. (eds) Tissue Engineering, Advances in Experimental Medicine and Biology, vol 585, Chapter 13, pp. 183-196).
The instant claims are discussed above.
USPN ‘761 claim 1 recites an ocular implant consisting of: (a) 20% w/w to 70% w/w of a therapeutic agent comprises and antibody; (b) 50-75% w/w of a photopolymerizable composition consisting of fragments or monomers polyalkylene glycol diacrylate (PEGDA), (c) 5-40% w/w of a biodegradable polymer consisting of poly(lactide-co-glycolide) (PLGA); (d) a photoinitiator comprising 1-[4-(2-hydroxethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone; and (e) a release modulating agent selected from hydroxypropyl methylcellulose (HPMC) or polyethylene glycol; wherein the composition, when photopolymerized to form an implant, is characterized by suppressing an initial burst release over a prolonged period greater than 1 to 9 months.
The difference between the instantly rejected claims and the claims of USPN ‘761 is that the claims of USPN ‘761 do not expressly claim the inclusion of aflibercept, or ranibizumab (instant claims 48-52), the degradation period (claims 53-56 & 58), the molecular weight of the first polymeric composition (PEG-DA), or the composition is injectable through a needle of 27 gauge.
DADEY ‘604 teaches ocular delivery of polymeric delivery formulations, as discussed above and incorporated herein by reference.
DADEY ‘305 teaches dehydrated hydrogel inclusion complex of bioactive agent with flowable drug delivery system, as discussed above and incorporated herein by reference.
KLIMAN teaches implantable drug delivery devices for long term delivery (weeks, months, years), as discussed above and incorporated herein by reference.
Baroli teaches that photopolymerizable systems have been proposed as good candidates for drug delivery, as discussed above and incorporated herein by reference.
Mieler et al. teaches thermoresponsive hydrogels for ocular drug delivery to the posterior segment of the eye. as discussed above and incorporated herein by reference.
SCHWARTZ teaches methods directed at treating retinal breaks with a nontoxic polymer, as discussed above and incorporated herein by reference.
It would have been prima facie obvious before the effective filing date of the claimed invention that the instantly rejected claims are an obvious variant of the claims of the claims of USPN ‘761 because claims of USPN ‘761 each include the same constituent ingredients for an ocular implant, where the prior art clearly teaches prolong delivery minimizes need for repeated invasive procedures (e.g. implantation in the eye), and each of aflibercept, ranibizumab, or bevacizumab were known ocular drugs (anti-VEGF agents for treatment of AMD). The skilled artisan would have been motivated to modify the claims of copending claims and produce the instantly rejected claim because sustained delivery of aflibercept, ranibizumab, or bevacizumab by an ocular implant would have minimized patient discomfort by minimizing implantation procedures. Furthermore, the skilled artisan would have had a reasonable expectation of success in producing the invention of the instantly rejected claims because it would have required no more than an ordinary level of skill in the art to produce an ocular implant per the claims of USPN ‘761.
Response to Arguments:
Applicant's arguments filed 06/15/2026 have been fully considered but they are not persuasive. Applicant argues that: “Applicants respectfully disagree for at least the same reasons discussed in the response to the rejection under 35 U.S.C. § 103, which are incorporated herein. - Withdrawal of the rejection is respectfully requested.” (p. 15, last paragraph).
In response the examiner argues the instant claims are not distinguished over the claims of copending ‘959 and/or ‘937, or USPN ‘761, Applicant’s arguments with respect to claim(s) GANCHEGUI have been considered but are moot because the new ground of rejection does not rely on GANCHEGUI, as applied in the prior rejection, of record for any teaching or matter specifically challenged in the argument; and Applicants other arguments are not convincing, as discussed above.
Conclusion
Claims 39, 44-56, and 58-62 are pending and have been examined on the merits. Claims 60 is rejected under 35 U.S.C. 112(a)(new matter); claims 39, 44-56, and 58-62 rejected under 35 U.S.C. 112(b); claims 39, 44-56, and 58-62 are rejected under 35 U.S.C. 103; and claims 39, 44-56, and 58-62 are (provisionally) rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Application Nos. 17/414,959 and 18/000,937 and USPN 12,642,761. No claims 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IVAN A GREENE whose telephone number is (571)270-5868. The examiner can normally be reached M-F, 8-5 PM PST.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619
Prosecution Insights