DETAILED ACTION
Status of the Claims
Claims 39, 44-56, 58 and 59 are pending in the instant application and are being examined on the merits in the instant application.
Request for Continued Examination
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/07/2025 has been entered.
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All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.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(b)
Claims 39, 44-56, 58 and 59 are 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, comprising: 99 to 60% (w/w) of a first polymeric biodegradable and photopolymerizable composition, 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 a second biodegradable polymer that is not photopolymerizable; a photoinitiator; and a therapeutic agent, wherein the composition is a homogeneous mixture (instant claim 39).
Applicant claims an ocular implant comprising: 99 to 60% (w/w) of a first polymeric biodegradable and photopolymerizable composition, 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 a second biodegradable polymer that is not photopolymerizable; a photoinitiator; and a therapeutic agent, wherein the composition is a homogeneous mixture, and wherein biodegradation of the ocular implant occurs over a period of about 6 months to about 12 months (instant claim 53).
Applicant added the new claim “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), for which the examiner finds no support.
Disclosure of the Instant Application:
Applicants’ arguments state that: “Support for the amendments and new claim may be found throughout the specification and claims as filed. For example, support for the amendments and new claim may be found in the Examples, at page 5, lines 6-7, and at pages 11-12 of the application as filed.” (p. 5, 1st paragraph).
Discussion:
The examiner finds no support for “wherein the composition is a homogenous mixture” for “A composition for preparing an ocular implant” (instant claim 39) or “wherein the composition is a homogenous mixture” for “An ocular implant” (instant claim 53). Particularly, applicant points to “the Examples, at page 5, lines 6-7, and at pages 11-12 of the application as filed” for support which is not found on these pages/lines. Similarly the examiner finds no support for new claim 59 reciting: “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.” Accordingly, the claims are rejected as introducing new matter and rejected under 35 U.S.C. 112(a), as failing to comply with the written description requirement. Applicant should point to support for the full scope of the claimed invention or cancel the new matter from the claims.
Claims 39, 44-56, 58 and 59 are rejected under 35 U.S.C. 103 as being unpatentable over GANCHEGUI (US 2010/0215720; published August, 2010) in view of DADEY (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).
Applicants Claims
Applicant claims an ocular composition for preparing an implant, comprising 99 to 60% (w/w) of a first polymeric composition that is biodegradable and photopolymerizable composition, 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 10,000 Dalton; a second biodegradable polymer that is not photopolymerizable; a photoinitiator; and a therapeutic agent (claim 1), and a composite implant comprising the same (claim 57).
Applicant further claims the first polymeric composition is copolymer or block copolymer of polyethylene glycol diacrylate (claims 40-43) having a molecular weight of between 200 to about 10,000 Da (claim 44). Applicant further claims the second biodegradable polymer is PLGA (claims 45-46).
Determination of the scope
and content of the prior art (MPEP 2141.01)
GANCHEGUI teaches implantable optical system (title, see whole document), and particularly “an implantable optical system comprising a central optical part and an annular anchoring part, where said annular part comprises animals cells, including human cells, that encourage the integration of the implant into the ocular tissue of the patient, as well as a system for dosing chemical compounds directed at a particular function, creating a stabilising microenvironment for the presence of the implant in the tissue.” (abstract)(instant claims 53-56, 58-59, an/the ocular implant).
GANCHEGUI teaches that “Some types of hydrogels can be polymerised both in vivo and in vitro in the presence of photoinitiators using visible or ultraviolet light, converting a monomeric liquid into a gel. These types of hydrogel have advantages over other conventional polymerisation techniques: control over polymerisation area and time, short curing times (from less than one second to a few minutes) at ambient or physiological temperatures and with a minimal production of heat. Another great advantage of photopolymerisation is that hydrogels can be created in situ from their aqueous precursors in a minimally invasive way, e.g. using laparoscopy equipment, catheters or subcutaneous injections with transdermic illumination.” ([0044]). And that: “Further, photopolymerisable hydrogels have the advantage that they enable the technique of photoencapsulation. This technique has also the great virtue that it enables the incorporation of cells into the initial phase of the gelification process, i.e., it allows mixing of cells and polymers in the liquid phase so that when the gelification of the material is started, the cells are already incorporated into its interior. This is a great advantage for tissue engineering as it solves one of the limitations of this technique, that is the low adhesion effectiveness of cells to the materials in the initial phase of inoculation.” ([0045]).
GANCHEGUI teaches that “In a preferred embodiment of the invention, the annular part and the central part comprise at least one hydrogel macromer in common, preferably an acrylic derivative of polyethylene glycol, such as polyethylene glycol diacrylate (PEGDA), to facilitate the subsequent sealing of both parts of the lens. In a particular embodiment, the hydro gel macromer can be copolymerising other monomers/polymers differentially in each part.” ([0048])(instant claims 39, 53, a first polymeric composition “a first polymeric composition that is biodegradable and photopolymerizable composition, selected from the group consisting of polyalkylene glycol diacrylate”).
GANCHEGUI teaches that “The annular component can also be constituted by biodegradable polymers, said polymers presenting biodegradable regions and preferably hydrolysable regions, such as ester, peptide, anhydride, orthoester or phosphoester links. Possible polymers susceptible to hydrolysis are the aliphatic polyesters, such as polyglycolic acid (PGA) and its copolymers, polylactic acid (PLA) and its copolymers, or polycaprolactone (PCL) and its copolymers […].” ([0051]). And further that: “In a preferred invention, the present invention uses polyesters for manufacture controlled release systems. Polyesters, such as poly(D-lactic-co-glycolic acid) and its derivatives are particularly attractive for polymeric controlled release systems due to their availability, biodegradability, lack of toxicity, bio-compatibility and by being easily combined with a wide variety of active principles.” ([0053])(instant claims 39, 53, “a second biodegradable polymer that is not photopolymerizable” – PLGA, PLA, PCL – claims 45-46).
GANCHEGUI teaches that: “As regards the active substances that can be incorporated into a controlled release system, these are mainly the anti-inflammatory, antibiotic, anti-viral, anti-tumour, etc., pharmaceuticals with application in ophthalmology.” ([0055]).
GANCHEGUI discloses: “A mixture comprising the polymeric PEGDA solution containing the photoinitiator and the PLGA spheres loaded with dexamethasone was prepared.” ([0092])(instant claims 39-43, 45-46 & 57).
GANCHEGUI teaches the “Samples with 80% constant aqueous content and 20% solid matter comprising 10% PEGDA, 5% [PLGA] spheres […].” (instant claim 47). Where the PEGDA and photoinitiator is disclosed as: “poly(ethylene glycol) diacrylate (PEGDA) was used with an average molecular weight of 3400 […] 2-hydroxy-1-[ 4-(hydroxyethoxy) phenyl]-2-methyl-1-propanone was used as the initiator” ([0083])(instant claims 39, 44, 53, “the first polymeric composition has a molecular weight of between about 200 to about 10,000 Da.”).
GANCHEGUI teaches “Obtaining the Controlled Release Therapeutic System” including the steps of “To do this, a determined quantity of dexamethasone was added to the polymer dissolved in dichloromethane (internal organic phase). The mixture was homogenised by ultrasound for one minute and added over a determined volume of water and emulsification agent (external aqueous phase). The organic/aqueous (0/W) emulsion was obtained by homogenising in a Polytron homogeniser at 5000 rpm for 2 minutes.” [emphasis added]([0085]-[0086]). And that: “FIG. 4. Schema of the photopolymerisation stage for obtaining the bicompartmental lens. 1) Filling the mould with the solutions A and B from Phases 1 and 2 (FIG. 3.) respectively; 2) Closure of the mould; 3) polymerisation and homogenisation of the sample; 4) Opening the lid and removing the separator; 5) Closure of the lid; 6) Polymerisation and homogenisation of the sample; 7) Opening the lid and extracting the bicompartmental lens.” [emphasis added]([0029])(instant claims 39, and 53, “wherein the composition is a homogenous mixture”).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of GANCHEGUI is that GANCHEGUI does not expressly teach the percentage of the first biodegradable and photopolymerizable composition (e.g. PEGDA) is in the range of 99-60 wt. % (claims 39 and 53), the active anti-VEGF agents (claims 48-52), or the degradation and/or release period (claims 53-56, 58).
DADEY 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 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 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 teaches the bioactive is a protein such as bevacizumab (AVASTIN)([0018])(instant claims 48, 49 & 52).
DADEY 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).” ([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]).
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).
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).
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).
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). The examiner notes that “transparent fluids” implies “a homogenous mixture” (MPEP §2144.01).
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).” (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)..
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 GANCHEGUI, DADEY, 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 GANCHEGUI, DADEY, 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).
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 11/07/2025 have been fully considered but they are not persuasive because Applicants have provided no substantive arguments over the cited prior art but provided the claim amendments.
Applicant argues that: “First, to function as described, the system of Ganchegui requires the PLGA spheres to degrade and leave holes for tissue infiltration to help anchor the device in place. See, for example, paragraph [0056] of Ganchegui. Paragraph [0057] of Ganchegui lists three distinct "variants" for the device, none of which include homogenously mixed components. Thus, modifying Ganchegui to remove such a key element would be contrary to the teachings of this reference. Furthermore, nothing in Dadey, Kliman, Mieler, Schwartz, nor Baroli suggests such a change to Ganchegui.” (p. 7, 7th paragraph). And that: “Second, if a skilled artisan did intermix the components of Ganchegui instead of relying on active agents separately encapsulated in pre-formed PLGA spheres, the system of Ganchegui would be rendered non-functional. Ganchegui first forms spheres of active agents in PLGA using an "oil phase/water phase (O/W) emulsion" technique before mixing with the PEGDA to facilitate mixing of the PLGA spheres and PEGDA. Otherwise, such compositions precipitate and separate once water is added, which is an essential component of the oil phase/water phase (O/W) emulsion used in Ganchegui's system. See, for example, paragraph [0061] and Example 1 of Ganchegui.” (paragraph bridging pp. 7-8). And: “Thus, one of ordinary skill would have had no "apparent reason" to modify Ganchegui to intermix the ingredients in a homogeneous mixture or to increase PEGDA amount, and/or to remove water from the system to arrive at the claimed compositions. Ganchegui unambiguously states, "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 amount of other components in the system of Ganchegui, including the aqueous component.” (p. 8, 2nd paragraph).
In response the examiner argues that GANCHEGUI teaches that: “The implantable optical system described may also be used in other types of ocular disorders, such as disorders of the lens, applied to the development of intra-ocular lenses.” And that: “The invention here described is susceptible to variations and modifications not specifically described in this patent application. However, the invention includes all these possible variations and modifications that derive from the state of the art and are therefore obvious to an expert in the field.” ([0080]-[0081]). It would have been prima facie obvious to modify the ocular implant of GANCHEGUI to combine a photopolymerizable polymer such as PEGDA and biodegradable polymer such as PLGA to form a controlled release formulation implantable in the eye. For example, 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). Mieler et al., an expert in the field, 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). The instantly rejected claims recite “A composition for preparing an ocular implant, comprising: […].” (claim 39). And “An ocular implant comprising […]” (claim 53). MPEP §2111.03 makes clear that “The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.” Therefore, the claimed composition(s) can include additional elements such as water (instant Specification describing hydrogels – p. 14, §PEGDA; p. 19 – “In one embodiment the aqueous medium is a combination of water and phosphate buffered saline (PBS). – p. 18, “ii) adding the mixture i) to an aqueous medium to form mixture ii)”. The examiner is interpreting the “99 to 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).
Further regarding the claimed amount of the “first polymeric biodegradable and photopolymerizable composition” (e.g. PEGDA), arguendo the prior art does not teach this amount, MPEP §2144.05 makes clear that: “Generally, differences in concentration or temperature will 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."” Based on the current record it is very clear that each of the claimed components were know for use in ocular delivery systems, and particularly for controlled/extended release formulations. Therefore simply modifying the amount of one constituent (e.g. PEGDA) relative to the prior art, would not be considered a basis for patentability as PEGDA was known for the very same utility, and general conditions for producing a PGDA/PLGA/photoinitator/therapeutic agent were would have been known to those having ordinary skill in the art (it is not inventive to discover the optimum or workable ranges by routine experimentation).
Applicant further notes that: “Applicant notes that similar arguments were made in the parent application U.S. Ser. No. 15/774,828 in response to a Non-Final office action filed on February 12, 2021. The arguments overcame the obviousness rejection using Ganchegui as the primary reference.”
In response the examiner advises Applicant that each case is examined on its own merits.
Applicant argues that: “nothing in Schwartz directs a person of skill in the art to the specific claimed range of 99-60% of the first polymeric biodegradable and photopolymerizable composition as claimed. The working examples in Schwartz use 10% or less of the photopolymerizable composition and col. 4, lines 35-37 is the single location in all of Schwartz where a concentration of greater than ~20% of the polymer precursor is contemplated. Also, there would have been no reason for one of ordinary skill in the art based on the disclosure of Schwartz (or any of the other secondary references) to modify Ganchegui to include 99 to 60% (w/w) of the first polymeric biodegradable and photopolymerizable composition, as recited in the claims. As discussed above, such a modification would require a dramatic increase in the PEGDA content proposed by Ganchegui which would necessarily require a decrease in the aqueous content, which is required in Guanchegui 's system at a high percentage.” (paragraph bridging pp. 9-10).
In response the examiner argues that disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. (MPEP §2123).
Applicant argues that: “Although Dadey is a secondary reference in the obviousness rejection, Applicant notes that Dadey itself has similar deficiencies as Ganchegui. Dadey is directed to a controlled release biodegradable polymer formulation that uses a 2-part system and that, similar to Ganchegui, there is no point in time when the Dadey system exists in a homogenous mixture. Part 1 of Dadey 's system consists of a PEG hydrogel and bioactive agent pre-formed into microparticles, nanoparticles, or fine powder, which are then dispersed into Part 2 of Dadey 's system (the biodegradable polymer and organic solvent mixture), as explained in paragraph [0013] of Dadey. Thus, Dadey does not teach a homogeneous mixture as claimed, but rather describes a system of preformed particles of PEG/bioactive agent lacking photoinitiator that are then dispersed in the bulk polymer/solvent system.” (p. 9, 2nd paragraph).
In response the examiner argues 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). The examiner notes that “transparent fluids” implies “a homogenous mixture” (MPEP §2144.01), and it would have been prima facie obvious to exclude “organic solvent” if not needed.
Applicant further argues that: “Also, the Dadey formulations do not include a photoinitiator dispersed in the solvent or in the final controlled release formulation. Rather the PEG acrylate is pre-polymerized using the photoinitiator so that the hydrogel matrix can be formed to enclose the bioactive agent in the inclusion complex particles. See, paragraph [0059] of Dadey. The resulting preformed hydrogel is then immersed in water for several days to remove unreacted monomer, which would also remove unreacted photoinitiator. The resulting hydrogel lacking photoinitiator, is dried, ground into powder (or subjected to a different microparticle formation process), infused with the bioactive agent, dried a second time, and then added to the bulk polymer/solvent system. See, Dadey at paragraphs [0046]-[005 l].” (p. 9, 3rd paragraph).
In response it is unclear how this argument would distinguish over the instantly rejected claims. It would have been within the ordinary level of skill in the art for a person having ordinary skill to recognize that “hydrophobic polymer (PLGA) could dissolve into a hydrophilic macro-monomer (PEGDM) without the need of organic solvents and then producing transparent fluids.” And simply to include a therapeutic agent and a photoinitiator – known for utility in crosslinking PEGDA or PEGDM – would have required no more than an ordinary level of skill in the art.
The examiner notes that the Examples in the instant Specification include “Poly(ethylene glycol) diacrylate (PEGDA) molecular weight (Mw) 258, 575 and 700 Da” (p. 22, line 6), therefore the examiner suggest narrowing the scope of the recited “molecular weight of about 200 to about 20,000 Dalton” (claims 39 & 53) to be more consistent with the Examples such as “between about 200 and about 1000 Da” or narrower (see Examples). Further the Specification indicates that: “It has been found, for the compositions and implants of the present invention, that an increase in molecular weight of the photopolymerizable compositions results in an increase in drug release rate. Without wishing to be bound by theory, it is believed that photopolymerizable compositions with lower molecular weights have higher crosslinking density and therefore slower drug release rates.” (p. 9, 5th paragraph).
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, 58 and 59 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Application Nos. 17/414,958 (claims 1-2, 8-9, and 17-20; hereafter ‘958), 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 GANCHEGUI (US 2010/0215720; published August, 2010); DADEY (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).
Instant claim 39 is discussed above.
Copending ‘958 claim 1 recites an ocular implant comprising: (a) at least 20% w/w of a therapeutic agent; (b) 50-75% w/w of a photopolymerizable composition consisting of fragments or monomers polyalkylene glycol diacrylate (PEGDA), and mixtures, copolymers, and block copolymers thereof, (c) 5% w/w of a biodegradable polymer selected from the group consisting of poly(lactide-co-glycolide) (PLGA) and mixtures, copolymers, and block copolymers thereof; (d) a photoinitiator comprising 1-[4-(2-hydroxethoxy)-phenyl]-2-hydroxy-2-methyl-1-propanone; wherein the implant is spherically, cylindrically, rod or bead-shaped; and wherein 75% of the therapeutic agent is released over 196 days.
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).
GANCHEGUI teaches implantable optical system, as discussed above and incorporated herein by reference.
DADEY 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. 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 ‘958, ‘959 and/or ‘937.
This is a provisional obviousness-type double patenting rejection.
Response to Arguments:
Applicant's arguments filed 11/07/2025 have been fully considered but they are not persuasive. Applicant argues that: “in pending application '958, a response to a Non-Final Office Action was filed on July 25, 2025, after the Final Office Action in the present application was mailed. In this response, the claims were amended to include, "a release modulating agent selected from hydroxypropyl methylcellulose (HPMC) and polyethylene glycol (PEG)," and "wherein the composition, when photopolymerized to form an implant, is characterized by suppressing an initial burst release of the therapeutic agent while providing sustained release over a prolonged period greater than 1 to 9 months." Based on this amendment in pending application '958 alone, Applicant asserts that the pending claims are not obvious over the pending application '958.” (p. 10, 4th paragraph).
In response the examiner notes that the instantly rejected claims recite “A composition for preparing an ocular implant, comprising: […].” (claim 39). And “An ocular implant comprising […]” (claim 53). MPEP §2111.03 makes clear that “The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.” Therefore, the claimed composition(s) can include additional elements such as HPMC or PEG, and the arguments do not distinguish the instantly rejected claims over the claims of ‘958.
Applicant further argues that: “Lastly, in pending application ' 959, a response to a Non-Final Office Action was filed on March 18, 2025, after the Final Office Action in the present application was mailed. In this response the claims were amended to include, "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 have a length of about 2mm; and wherein the implant maintains a zero order release over 180 days." Based on this amendment in pending application '959 alone, Applicant asserts that the pending claims are not obvious over the pending application '959.” (p. 10, last paragraph).
In response the examiner argues the instant claims are not distinguished over the claims of ‘959 as the include open-ended language, as discussed above.
Conclusion
Claims 39, 44-56, 58 and 59 are pending and have been examined on the merits. Claims 39, 44-56, 58 and 59 are rejected under 35 U.S.C. 112(a); claims 39, 44-56, 58 and 59 are rejected under 35 U.S.C. 103; and claims 39-56 and 58 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Application Nos. 17/414,958, 17/414,959 and 18/000,937. No claims allowed at this time.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619