DETAILED ACTION
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/05/2026 has been entered.
Status of Application
The response filed 05/05/2026 has been received, entered and carefully considered. The response affects the instant application accordingly:
Claims 1, 3, 6, 23, 27, 32 have been amended.
Claims 2, 4-5, 24-26, 33-34 has been cancelled.
Claims 29-35 has been added.
A certified copy of the foreign priority document is submitted.
A declaration by Riad Sherif is presented.
Claims 1, 3, 6, 17-18, 20-23, 27-32, 35 are pending.
Claims 1, 3, 6, 17-18, 20-23, 27-32, 35 are present for examination at this time.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
All grounds not addressed in the action are withdrawn or moot as a result of amendment or declaration.
New grounds of rejection are set forth in the current office action as a result of amendment.
New Grounds of Rejection
Due to the amendment of the claims the new grounds of rejection are applied:
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 3, 6, 17-18, 20-23, 27-32 are rejected under 35 U.S.C. 103 as being unpatentable over Loftsson et al. (WO 2021/001366) in view of National Health Service (NHS) (How and when to use dexamethasone eye drops).
Rejection:
Loftsson et al. teaches treating eye diseases like diabetic macular edema, with an aqueous corticosteroid composition comprising cyclodextrin and additives like sodium thiosulfate (abstract, Page 11 line 20-21, Page 12 line 1-10, Page 25 line 18-21). The corticosteroid is preferably dexamethasone and be from 0.5-5% w/v of the composition- more particularly 1.5-3% w/v (Page 5 line 15-20, Page 6 line 1-5, Page 16 line 25-Page 17 line 25). The cyclodextrin can be γ-cyclodextrin and be from 12-25%w/v (Page 6 line 5-15, Page 17 line 27-Page 18 line 7). The aqueous composition can have the drug and cyclodextrin as a solid complex with a D50 of about 1-about 25um and more particularly about 1um-about 10um as particle sizes below about 10um prevents eye irritation (Page 9 line 1-13, Page 10 line 1-5). The composition can comprise a preservative or be preservative-free (Page 13 line 1-10, Page 22 line 31-32). The composition can have a stabilizing agent like disodium edetate from 0-1%w/v (Page 13 line 10-14), an electrolyte like sodium chloride in various amounts including 0.2-1%w/v (Page 13 line 15-20), a polymer like poloxamers which are useful as stabilizers (Page 14 line 1-20, Page 15 line 1-20), and the pH is preferably between 4.5-6 (claims 13 and 23, Page 12 line 11-20). The aqueous composition can be stored in plastic vials (Page 20 line 1-3), and the treatment is useful for patients with no or inadequate response to VEGF inhibitors including those with retinal thickening in the affected eye due to diabetic macular edema (VEGF inhibitor naïve, Page 27 line 13-20).
Loftsson teaches methods of treating diabetic macular edema (DME) with an eyedrop formulation with 1.5%w/v dexamethasone with a preferred dosing of 1-6 drops a day for a duration of at least 6, 7, 8, 9, 10, 11, or 12 weeks; the preferred eye drop formulation contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer;
0-0.2% of stabilizing agent, for example 0.1% of disodium edetate;
0-1% of electrolyte, for example 0.57% of sodium chloride;
0% to 0.6% of an additive to prevent the oxidation of the dexamethasone, for example between 0.1% and 0.5%, or between 0.2% and 0.4%, of an additive to prevent the oxidation of the corticosteroid, typically sodium thiosulfate;
and water; wherein the % are w/v (Page 25 line 33-Page 26 line 23).
A preferred embodiment of the method has the eye drop formulation contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v (Page 21).
The central macular thickness (CMT) assessed by SD-OCT may be significantly reduced after 12 weeks of treatment in a patient suffering from DME, such as more than 10% CMT as measured from baseline, and have improved pin hole visual acuity from baseline to at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME (Page 27 line 4-11), and the patient is a human patient and teaches a Clinical Study 1, dexamethasone 1.5 microsuspension 3x/day for 12 weeks for treatment of diabetic macular edema ( (Page 27 line 21, Page 29-30, Page 35-36, see full document specifically areas cited).
While Loftsson et al. does not teach the exact claimed mean ETDRS letters of improvement (i.e. at least 5 ETDRS letters, at least 5 Early Treatment Diabetic Retinopathy Study letters) and pH and sodium thiosulfate (instant claim 35), Loftsson et al. does teach the range that embraces it as the pH range is 4.5-6 and the sodium thiosulfate is from 0.2-0.4% and the central macular thickness (CMT) can be significantly reduced after 12 weeks of treatment in a patient suffering from DME, such as more than 10% CMT as measured from baseline, and have improved pinhole visual acuity from baseline to at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME (Page 27 line 4-11) which embraces the claimed values where it would be prima facie obvious to optimize the pH and the amount of sodium thiosulfate and the amount of improvement by the amount of treatment as a means to attain the desired therapeutic profile with a reasonable expectation of success. It is also prima facie obvious to optimize the components like cyclodextrin within the ranges taught to arrive at the breath claimed (i.e. 12-16% in addition to 14%) as a means for attaining the desired therapeutic profile.
While Loftsson et al. does not expressly teach the exact claimed dosing regimen but Loftsson et al. does teach treating diabetic macular edema by dosing of 1-6 drops a day for a duration of at least 6, 7, 8, 9, 10, 11, or 12 weeks.
NHS (National Health Service) teaches that dexamethasone eye drops are known to be usually given at one eyedrop 4-6 times a day and once your symptoms are better the doctor may have you reduce the dose before stopping completely (Dosage, How long to use eye drops).
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have an initial dosing regimen and then lower the dosing regimen as suggested by NHS and produce the claimed invention; as it is prima facie obvious to dose dexamethasone in its known regimen as taught by NHS and is embraced by Loftsson et al. (i.e. 1 drop 6x/day) and to reduce the dose as the symptoms improve as established by NHS as embraced by Loftsson et al. (i.e. 1 drop 1-3x/day) for as long as needed as described by Loftsson et al. to achieve the desired therapeutic outcome (i.e. 6 weeks or more (e.g. 2 weeks until symptoms improve and 6 weeks or more at reduced dose until desired therapeutic outcome is achieved) with a reasonable expectation of success absent evidence of criticality for the recited dose and duration. While the prior art does not expressly recite the amount of reduction of the central subfield thickness (CST), it does teach the reduction of the central macular thickness (CMT) which embraces the central subfield thickness which is to the thickness of center of the macula (fovea) wherein as there is a reduction in the CMT it would have a reduction of the CST (being the center); additionally as the same ophthalmic eyedrop is being given for the recited treatment it would be expected to have the same amount of reduction after treatment as addressed by the instant specification.
Response to Arguments:
Applicant's arguments are centered on the assertion that diabetic macular edema is difficult to treat and that current therapies all involve injection into the eye to be able to reach the retina including intravitreal injection of anti-VEGF antibodies like Lucentis or Eylea and Ozrdex which is a 700mg dexamethasone intravitreal implant, and that there is no current remedy on the market today that accomplishes this topically. Applicant also asserts unexpected results and cites the Sherif declaration, that the case law of Janssen Pharms v Mylan Labs, Ltd support patentability of the present claims as the Federal Circuit concluded that changes of a dosage form over the prior rt dosage form was not obvious, and that the NHS article refers to the use of dexamethasone for anterior disorders not to diabetic macular edema.
This is fully considered but not persuasive.
The assertion that diabetic macular edema is difficult to treat and that current therapies all involve injection into the eye and that there is no current remedy on the market today that accomplishes this topically is directed to commercial success which is not the basis for patentability – patentability is with regards to what is known in the prior art and what is prima facie obvious with regards to prior art, not to commercial availability of treatments. If directed to secondary considerations for unmet need, this is directed to the assertion of unexpected results and the Sherif declaration which does not contain all the content previously recited in Applicant arguments including the graphics but does address that:
-the regimen used in the Phase 2 trial was described in Loftsson (WO’366) where the OCS-01 formulation was given one drop 3x/day for 12 weeks (the clinical study 1 of Loftsson) and
- the regimen used in the Stage 1 of the Phase 2/3 DIAMOND-1 trial are that of the instant application where the OCS-01 formulation was given in an induction phase of 6 drops a day for 6 weeks followed by a maintenance phase of 3 drops a day for 6 weeks.
The Phase 2 trial with the constant dosing of the OCS-01 formulation at one drop 3x/day for 12 weeks had an increase in mean BCVA letter score of 2.9 letters which is a 2.6 LS mean from baseline at week 12 (item 10 of the declaration),
The Phase 2/3I Clinic Trial administered the OCS-1 formulation for diabetic macular edema which is the following formulation from the specification
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was topically given six drops a day for the first six week of therapy and then maintenance dose of 3x/day for six weeks (to get to week 12) had results in Table 1 with a 7.2 letter gain in BCVA at week 6 which is an LS mean increase of 7.4 (p=0.007) and 7.6 letter gain in BCVA at week 12 which is a LS mean increase of 7.7 (p=0.016), and with 25.3% patient gained greater than 15 letters at week 6 (p=0.015) and 27.4% patient gained greater than 15 letters at week 12 (p=0.008).
This is unexpected and demonstrates that the specific regimen of the specific OCS-1 formulation of
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when administered for the treatment of DME at 6 drops/day for six weeks followed by a maintenance dose of 3 drops/day for 6 weeks for a total 12 weeks of therapy are unexpected as there was a 7.2 letter gain in BCVA at week 6 (p=0.007 if a p values of <0.007 which would be statistically significant) and unexpected as it is also greater than double the letter gain in BCVA at 3 drops/day in as described in the constant dosing in Phase 2 and Loftsson (WO’366) example. There was a final showing of 7.6 letter gain in BCVA at week 12 at the maintenance dose which is unexpected as the maintenance dose of 3 drops/day for 6 weeks would be expected to slow the decline of the gain made the first 6 weeks or perhaps hold/maintain it, as it is greater than double the letter gain in BCVA at 3 drops/day in as described in the constant dosing in Phase 2 and Loftsson (WO’366) example which showed some improvement of 2.9 in the ETDRS letters at 3 drops/day after 12 weeks; which would not have been expected but the breath claimed is broader than the showing and claims must be commensurate in scope with the presentation of unexpected results to overcome the prior art rejection. Wherein this rejection to claim 35 which is the scope of the showing is overcome but subject to the rejection below.
As for Applicants arguments with regards to case law of Janssen Pharms v Mylan Labs, Ltd, it is not persuasive as the merits of the cases are not the same as those in the instant case, prosecution of previous cases have no bearing on the instant case as each application is to be treated on its own merits. Additionally details of the case are not those of the instant claims as it is not to changes to dosage form as asserted but that the prior art in the case was to starting a medication at 1 month dose for at least four months before and ramping to a 3 month dose was distinctly different (not obvious) from giving a second reinitiation dose of 1month after missing a 3 month dose and then giving a 3month dose without stabilization; is not the same fact pattern presented.
As for the assertion that the NHS article refers to the use of dexamethasone for anterior disorders not to diabetic macular edema, this is not persuasive. The assertion is not reflective of the reference. Contrary to the assertion, the NHS article does not refer to the use of dexamethasone for anterior eye disorders. This also with regards to the assertion in the Sherif declaration as it is an opinion not supported by NHS reference. Additionally, the NHS reference is presented merely to show that dexamethasone is known to be usually given at one eyedrop 4-6 times a day and once your symptoms are better the doctor may have you reduce the dose before stopping completely wherein it is obvious to dose dexamethasone in its known regimen as taught by NHS and is embraced by Loftsson et al. (i.e. 1 drop 6x/day) and to reduce the dose as the symptoms improve as established by NHS as embraced by Loftsson et al. (i.e. 1 drop 1-3x/day) for as long as needed to achieve the desired therapeutic outcome (i.e. 6 weeks or more (e.g. 2 or 6 weeks until symptoms improve and 6 weeks or more at reduced dose until desired therapeutic outcome is achieved) with a reasonable expectation of success absent evidence of criticality for the recited dose and duration which has not been presented for the breath claimed.
Accordingly, the rejection stands.
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Loftsson et al. (WO 2021/001366) in view of National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Hutton (Oculis announces positive top line results from Phase 3 trial of OCS-01 drops for diabetic macular edema).
It is noted that Hutton falls under a 102(a)(1) date within a year of the instant priority date wherein the reference fall within the grace period and 102(b)(1) exceptions would apply.
Rejection:
The teachings of Loftsson et al. in view of NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop embodiment that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
Loftsson et al. in view of NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Hutton teaches that dexamethasone eyedrops (OCS-01) was given to diabetic macular edema patients six times daily for a six week loading phase and then 3 times daily for a six week maintenance phase; wherein there was a mean BCVA ETDRS score of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the dexamethasone eyedrop as suggested by Hutton and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success as it show a significant/unexpected improvement in the disease condition.
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Loftsson et al. (WO 2021/001366) in view of National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Oculis (Rethinking Ophthalmology –Oculis R&D Retina Day presentation 7/11/2023) or alternatively Oculis (Rethinking Ophthalmology – Investor Webcast 4/13/2023) or Oculis (Rethinking Ophthalmology –Jefferies Healthcare Conference 6/9/2023), or Tadayoni et al. (A 12-week Phase 2/3 Double-masked, Randomized, Multicenter Study of OCS-01 OPTIREACH Technology Topical Dexamethasone Eye Drops in Subjects with Diabetic Macular Edema (DME): Efficacy and Safety Findings).
It is noted that the secondary references to Oculis and Tadayoni et al. fall under 102(a)(1) dates within a year of the instant priority date wherein the references fall within the grace period and 102(b)(1) exceptions would apply.
Rejection:
The teachings of Loftsson et al. in view of NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop embodiment that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
Loftsson et al. in view of NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Oculis (Rethinking Ophthalmology - Oculis R&D Retina Day) teaches that dexamethasone eyedrops 1.5%(15mg/ml, OCS-01) was given to diabetic macular edema patients six times daily for a six weeks and then 3 times daily for a six weeks (loading dose and then maintenance dose); wherein there was a mean BCVA ETDRS endpoint with statistically significant including scores of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%, Pages 7-8, 11-12, 15-20). Alternatively, the similar teachings are found in Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al. (Pages 3, 5, 11). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the taught dexamethasone eyedrop as suggested by Oculis (Rethinking Ophthalmology -Investor Webcast) or alternatively Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al.; and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success for show a significant/unexpected improvement in the disease condition.
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 § 2146 et seq. 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, 6, 17-18, 20-23, 27-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 26-27 of U.S. Patent No. 12097209 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops).
The patented claims are directed to the method of treating diabetic macular edema with the topical administration from a plastic container with an aqueous ophthalmic composition comprising
i) 1.5% w/v of dexamethasone;
ii) 14% w/v of γ-cyclodextrin;
iii) 2.5% w/v of poloxamer 407;
iv) 0.1% w/v of disodium edetate;
v) 0.57% w/v of sodium chloride;
vi) 0.2-0.4% w/v of sodium thiosulfate; and,
vii) water; wherein the composition comprises a microsuspension comprising solid complexes of dexamethasone and γ-cyclodextrin (has no preservative).
The patented claims does not expressly teach the instant claimed dosing regimen, pH, the size of the solid dexamethasone/cyclodextrin complex, and usefulness for VEGF naïve patients; but does teach the treatment of diabetic macular edema with the aqueous dexamethasone/γ-cyclodextrin complex formulation.
Loftsson et al. teaches treating diabetic macular edema with the same formulation (Page 21, Page 25 line 33-Page 26 line 23), that the pH is preferably between 4.5-6 (claims 13 and 23, Page 12 line 11-20), that the preferred dosing of 1.5%w/v dexamethasone is 1-6 drops a day for a duration of at least 6, 7, 8, 9, 10, 11, or 12 weeks. Loftsson et al. also teaches that the solid complex of the drug and cyclodextrin has a D50 more particularly about 1um-about 10um as having it less than 10um prevents irritation of the eye (Page 9 line 1-13, Page 10 line 1-5), that the treatment is useful for patients with no or inadequate response to VEGF inhibitors (VEGF inhibitor naïve, Page 27 line 13-20) including those with retinal thickening in the affected eye due to diabetic macular edema, and that the central macular thickness (CMT) can be significantly reduced after 12 weeks of treatment in a patient suffering from DME, such as more than 10% CMT as measured from baseline, and have improved pin hole visual acuity from baseline to at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME (Page 27 line 4-11), and the patient is a human patient (Page 27 line 21, Page 29-30, Page 35-36).
NHS (National Health Service) teaches that dexamethasone eye drops are known to be usually given at one eyedrop 4-6 times a day and once your symptoms are better the doctor may have you reduce the dose before stopping completely (Dosage, How long to use eye drops).
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have an initial dosing regimen and then lower the dosing regimen of the formulation, a known pH of the formulation, a known size of the solid dexamethasone/cyclodextrin complex, and useful for a VEGF naïve subject as suggested by Loftsson et al. and NHS and produce the claimed invention; as it is prima facie obvious to dose dexamethasone in its known regimen as taught by Loftsson et al. and NHS (i.e. 1 drop 6x/day) and to reduce the dose as the symptoms improve as established by NHS within the known parameters described by Loftsson et al. (i.e. 1 drop 1-3x/day) for as long as needed to achieve the desired therapeutic outcome (i.e. 6 weeks or more (e.g. 2 weeks until symptoms improve and 6 weeks or more at reduced dose until desired therapeutic outcome is achieved) in patients like VEGF naïve patients including those with retinal thickening in the affected eye due to diabetic macular edema, with a reasonable expectation of success absent evidence of criticality for the recited dose and duration. It is also prima facie obvious to optimize the pH of the formulation within its known range (4.5-6) and arrive at the recited values as a means of attain the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values.
While the patented claims do not expressly recite the D50 of the drug/cyclodextrin complex, the prior art teaches that the solid complex of the drug/cyclodextrin can have a D50 of about 1um-about 10um wherein it is prima facie obvious to formulate the solid drug/cyclodextrin complex in this known range as having it less than 10um prevents irritation of the eye which is desirable with a reasonable expectation of success.
While the exact claimed mean ETDRS letters of improvement or central subfield thickness (CST) are not recited, the reduction of the central macular thickness (CMT) is embraced by the taught range (reduced after 12 weeks of treatment with the recited formulation in a patient suffering from DME by at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME) where it would be prima facie obvious to optimize the amount of improvement by the amount of treatment as a means to attain the desired therapeutic profile with a reasonable expectation of success. As there is a reduction in the CMT it would implicitly have a reduction of the CST (being the center of the macula); additionally as the same ophthalmic eyedrop is being given for the recited treatment it would be expected to have the same amount of reduction in CST after treatment as addressed by the instant specification.
Response to Arguments:
Applicant's arguments are centered on the assertion the instant claims are nonobvious over Loftsson and the NHS and the assertion of case law which are addressed above.
Accordingly, the rejection stands.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 26-27 of U.S. Patent No. 12097209 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Hutton (Oculis announces positive top line results from Phase 3 trial of OCS-01 drops for diabetic macular edema).
It is noted that Hutton falls under a 102(a)(1) date within a year of the instant priority date wherein the reference fall within the grace period and 102(b)(1) exceptions would apply.
The teachings of the patented claims in view of Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop formulation that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The patented claims in view of Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Hutton teaches that dexamethasone eyedrops (OCS-01) was given to diabetic macular edema patients six times daily for a six week loading phase and then 3 times daily for a six week maintenance phase; wherein there was a mean BCVA ETDRS score of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the dexamethasone eyedrop as suggested by Hutton and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success as it show a significant/unexpected improvement in the disease condition.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 26-27 of U.S. Patent No. 12097209 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Oculis (Rethinking Ophthalmology –Oculis R&D Retina Day presentation 7/11/2023) or alternatively Oculis (Rethinking Ophthalmology – Investor Webcast 4/13/2023) or Oculis (Rethinking Ophthalmology –Jefferies Healthcare Conference 6/9/2023), or Tadayoni et al. (A 12-week Phase 2/3 Double-masked, Randomized, Multicenter Study of OCS-01 OPTIREACH Technology Topical Dexamethasone Eye Drops in Subjects with Diabetic Macular Edema (DME): Efficacy and Safety Findings).
It is noted that the secondary references to Oculis and Tadayoni et al. fall under 102(a)(1) dates within a year of the instant priority date wherein the references fall within the grace period and 102(b)(1) exceptions would apply.
Rejection:
The teachings of the patented claims in view of Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop embodiment that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The patented claims in view of Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Oculis (Rethinking Ophthalmology - Oculis R&D Retina Day) teaches that dexamethasone eyedrops 1.5%(15mg/ml, OCS-01) was given to diabetic macular edema patients six times daily for a six weeks and then 3 times daily for a six weeks (loading dose and then maintenance dose); wherein there was a mean BCVA ETDRS endpoint with statistically significant including scores of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%, Pages 7-8, 11-12, 15-20). Alternatively, the similar teachings are found in Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al. (Pages 3, 5, 11). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the taught dexamethasone eyedrop as suggested by Oculis (Rethinking Ophthalmology -Investor Webcast) or alternatively Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al.; and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success for show a significant/unexpected improvement in the disease condition.
Claims 1, 3, 6, 17-18, 20-23, 27-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-17 of U.S. Patent No. 12097209 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops).
The patented claims are directed to the method of treating diabetic macular edema with the topical administration from a plastic container with an aqueous ophthalmic composition comprising
i) 1-4% w/v of dexamethasone;
ii) 5-25% w/v of γ-cyclodextrin;
iii) 2.2-2.8% w/v of poloxamer;
iv) 0-0.2% w/v of disodium edetate;
v) 0-1% w/v of electrolyte;
vi) 0.1-0.5% w/v of sodium thiosulfate; and,
vii) water; wherein the composition comprises a microsuspension comprising solid complexes of dexamethasone and γ-cyclodextrin (has no preservative).
While the patented claims do not recite the exact claimed values for the components, they do embrace the claimed ranges wherein it would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize within the taught range and arrive at the claimed values as a means of attaining the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values.
The patented claims does not expressly teach the instant claimed dosing regimen, pH, the size of the solid dexamethasone/cyclodextrin complex, the electrolyte to be sodium chloride, and usefulness for VEGF naïve patients; but does teach the treatment of diabetic macular edema with the aqueous dexamethasone/γ-cyclodextrin complex formulation.
Loftsson et al. teaches treating diabetic macular edema with the same formulation and an embodiment to a specific formulation within the instant claims (Page 21, Page 25 line 33-Page 26 line 23), that the poloxamer can be poloxamer 407, that the pH is preferably between 4.5-6 (claims 13 and 23, Page 12 line 11-20), that the preferred dosing of 1.5%w/v dexamethasone is 1-6 drops a day for a duration of at least 6, 7, 8, 9, 10, 11, or 12 weeks. Loftsson et al. also teaches that the solid complex of the drug and cyclodextrin has a D50 more particularly about 1um-about 10um as having it less than 10um prevents irritation of the eye (Page 9 line 1-13, Page 10 line 1-5), that the electrolyte can be sodium chloride, that the treatment is useful for patients with no or inadequate response to VEGF inhibitors including those with retinal thickening in the affected eye due to diabetic macular edema (VEGF inhibitor naïve, Page 27 line 13-20), and that the central macular thickness (CMT) can be significantly reduced after 12 weeks of treatment in a patient suffering from DME, such as more than 10% CMT as measured from baseline, and have improved pin hole visual acuity from baseline to at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME (Page 27 line 4-11), and the patient is a human patient (Page 27 line 21, Page 29-30, Page 35-36).
NHS (National Health Service) teaches that dexamethasone eye drops are known to be usually given at one eyedrop 4-6 times a day and once your symptoms are better the doctor may have you reduce the dose before stopping completely (Dosage, How long to use eye drops).
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have an initial dosing regimen and then lower the dosing regimen of the formulation, a known pH of the formulation, a known size of the solid dexamethasone/cyclodextrin complex, that the electrolyte can be sodium chloride, and useful for a VEGF naïve subject as suggested by Loftsson et al. and NHS and produce the claimed invention; as it is prima facie obvious to dose dexamethasone in its known regimen as taught by Loftsson et al. and NHS (i.e. 1 drop 6x/day) and to reduce the dose as the symptoms improve as established by NHS within the known parameters described by Loftsson et al. (i.e. 1 drop 1-3x/day) for as long as needed to achieve the desired therapeutic outcome (i.e. 6 weeks or more (e.g. 2 weeks until symptoms improve and 6 weeks or more at reduced dose until desired therapeutic outcome is achieved) in patients like VEGF naïve patients including those with retinal thickening in the affected eye due to diabetic macular edema, with a reasonable expectation of success absent evidence of criticality for the recited dose and duration. It is also prima facie obvious to optimize the pH of the formulation within its known range (4.5-6) and arrive at the recited values as a means of attain the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values; and prima facie obvious to utilize a known electrolyte like sodium chloride for the formulation with a reasonable expectation of success.
While the patented claims do not expressly recite the D50 of the drug/cyclodextrin complex, the prior art teaches that the solid complex of the drug/cyclodextrin can have a D50 of about 1um-about 10um wherein it is prima facie obvious to formulate the solid drug/cyclodextrin complex in this known range as having it less than 10um prevents irritation of the eye which is desirable with a reasonable expectation of success.
While the exact claimed mean ETDRS letters of improvement or central subfield thickness (CST) are not recited, the reduction of the central macular thickness (CMT) is embraced by the taught range (reduced after 12 weeks of treatment with the recited formulation in a patient suffering from DME by at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME) where it would be prima facie obvious to optimize the amount of improvement by the amount of treatment as a means to attain the desired therapeutic profile with a reasonable expectation of success. As there is a reduction in the CMT it would implicitly have a reduction of the CST (being the center of the macula); additionally as the same ophthalmic eyedrop is being given for the recited treatment it would be expected to have the same amount of reduction in CST after treatment as addressed by the instant specification.
Response to Arguments:
Applicant's arguments are centered on the assertion the instant claims are nonobvious over Loftsson and the NHS and the assertion of case law which are addressed above.
Accordingly, the rejection stands.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-17 of U.S. Patent No. 12097209 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Hutton (Oculis announces positive top line results from Phase 3 trial of OCS-01 drops for diabetic macular edema).
It is noted that Hutton falls under a 102(a)(1) date within a year of the instant priority date wherein the reference fall within the grace period and 102(b)(1) exceptions would apply.
The teachings of the patented claims in view of Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop formulation that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The patented claims in view of Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Hutton teaches that dexamethasone eyedrops (OCS-01) was given to diabetic macular edema patients six times daily for a six week loading phase and then 3 times daily for a six week maintenance phase; wherein there was a mean BCVA ETDRS score of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the dexamethasone eyedrop as suggested by Hutton and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success as it show a significant/unexpected improvement in the disease condition.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-17 of U.S. Patent No. 12097209 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Oculis (Rethinking Ophthalmology –Oculis R&D Retina Day presentation 7/11/2023) or alternatively Oculis (Rethinking Ophthalmology – Investor Webcast 4/13/2023) or Oculis (Rethinking Ophthalmology –Jefferies Healthcare Conference 6/9/2023), or Tadayoni et al. (A 12-week Phase 2/3 Double-masked, Randomized, Multicenter Study of OCS-01 OPTIREACH Technology Topical Dexamethasone Eye Drops in Subjects with Diabetic Macular Edema (DME): Efficacy and Safety Findings).
It is noted that the secondary references to Oculis and Tadayoni et al. fall under 102(a)(1) dates within a year of the instant priority date wherein the references fall within the grace period and 102(b)(1) exceptions would apply.
Rejection:
The teachings of the patented claims in view of Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop embodiment that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The patented claims in view of Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Oculis (Rethinking Ophthalmology - Oculis R&D Retina Day) teaches that dexamethasone eyedrops 1.5%(15mg/ml, OCS-01) was given to diabetic macular edema patients six times daily for a six weeks and then 3 times daily for a six weeks (loading dose and then maintenance dose); wherein there was a mean BCVA ETDRS endpoint with statistically significant including scores of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%, Pages 7-8, 11-12, 15-20). Alternatively, the similar teachings are found in Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al. (Pages 3, 5, 11). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the taught dexamethasone eyedrop as suggested by Oculis (Rethinking Ophthalmology -Investor Webcast) or alternatively Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al.; and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success for show a significant/unexpected improvement in the disease condition.
Claims 1, 3, 6, 17-18, 20-23, 27-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15, 18-25 of U.S. Patent No. 12097209 in view of Genentech (Diabetic Macular Edema (DME) Fact Sheet) and Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops).
Patented claim 19 is directed to the method of treating diabetic macular edema with the topical administration of an aqueous ophthalmic composition comprising
i) 1.5% w/v of dexamethasone;
ii) 14% w/v of γ-cyclodextrin;
iii) 2.5% w/v of poloxamer 407;
iv) 0.1% w/v of disodium edetate;
v) 0.57% w/v of sodium chloride;
vi) 0.2-0.4% w/v of sodium thiosulfate; and,
vii) water; wherein the composition comprises a microsuspension comprising solid complexes of dexamethasone and γ-cyclodextrin (has no preservative). Its dependent claims recite the size of the solid complexes to have a D50 of about 1-10um, sodium thiosulfate to be 0.3% and the subject to be VEGF inhibitor naïve.
Patented claim 1 is directed to the method of treating diabetic retinopathy with the topical administration from a plastic container with an aqueous ophthalmic composition comprising
i) 1-4% w/v of dexamethasone;
ii) 5-25% w/v of γ-cyclodextrin;
iii) 2.2-2.8% w/v of poloxamer;
iv) 0-0.2% w/v of disodium edetate;
v) 0-1% w/v of electrolyte;
vi) 0.1-0.5% w/v of sodium thiosulfate; and,
vii) water; wherein the composition comprises a microsuspension comprising solid complexes of dexamethasone and γ-cyclodextrin (has no preservative).
Its dependent claims recite γ-cyclodextrin at 14%w.v, poloxamer at 2.5%w/v, disodium edetate at 0.1%, the electrolyte to be sodium chloride at 0.57%w/v, the size of the solid complexes to have a D50 of about 1-10um, sodium thiosulfate to be 0.3% and the subject to be VEGF inhibitor naïve.
While patented claim 1 does not recite the exact claimed values for the components, they do embrace the claimed ranges wherein it would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize within the taught range and arrive at the claimed values as a means of attaining the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values.
The patented claims does not expressly teach the instant claimed dosing regimen for diabetic macular edema or pH; but does teach the treatment of diabetic retinopathy with the aqueous dexamethasone/γ-cyclodextrin complex formulation.
Genentech teaches that diabetic retinopathy that worsens can lead to diabetic macular edema, and that diabetic macular edema can occur at any stage of diabetic retinopathy although more likely as the disease progresses (paragraph 1-3).
Loftsson et al. teaches treating diabetic macular edema with the same formulation (Page 21, Page 25 line 33-Page 26 line 23), that the pH is preferably between 4.5-6 (claims 13 and 23, Page 12 line 11-20), that the preferred dosing of 1.5%w/v dexamethasone is 1-6 drops a day for a duration of at least 6, 7, 8, 9, 10, 11, or 12 weeks. Loftsson et al. also teaches that the solid complex of the drug and cyclodextrin has a D50 more particularly about 1um-about 10um as having it less than 10um prevents irritation of the eye (Page 9 line 1-13, Page 10 line 1-5), that the treatment is useful for patients with no or inadequate response to VEGF inhibitors including those with retinal thickening in the affected eye due to diabetic macular edema (VEGF inhibitor naïve, Page 27 line 13-20) including those with retinal thickening in the affected eye due to diabetic macular edema, and that the central macular thickness (CMT) can be significantly reduced after 12 weeks of treatment in a patient suffering from DME, such as more than 10% CMT as measured from baseline, and have improved pin hole visual acuity from baseline to at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME (Page 27 line 4-11), and the patient is a human patient (Page 27 line 21, Page 29-30, Page 35-36).
NHS (National Health Service) teaches that dexamethasone eye drops are known to be usually given at one eyedrop 4-6 times a day and once your symptoms are better the doctor may have you reduce the dose before stopping completely (Dosage, How long to use eye drops).
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat diabetic macular edema with an initial dosing regimen and then lower the dosing regimen of the formulation and a known pH of the formulation as suggested by Genentech and Loftsson et al. and NHS and produce the claimed invention; as it is prima facie obvious to not only treat diabetic retinopathy but its known complication of diabetic macular edema as addressed by Genentech with the taught dexamethasone in its known regimen as taught by Loftsson et al. and NHS (i.e. 1 drop 6x/day) and to reduce the dose as the symptoms improve as established by NHS within the known parameters described by Loftsson et al. (i.e. 1 drop 1-3x/day) for as long as needed to achieve the desired therapeutic outcome (i.e. 6 weeks or more (e.g. 2 weeks until symptoms improve and 6 weeks or more at reduced dose until desired therapeutic outcome is achieved) in patients with a reasonable expectation of success absent evidence of criticality for the recited dose and duration. It is also prima facie obvious to optimize the pH of the formulation within its known range (4.5-6) and arrive at the recited values as a means of attain the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values.
While the exact claimed mean ETDRS letters of improvement or central subfield thickness (CST) are not recited, the reduction of the central macular thickness (CMT) is embraced by the taught range (reduced after 12 weeks of treatment with the recited formulation in a patient suffering from DME by at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME) where it would be prima facie obvious to optimize the amount of improvement by the amount of treatment as a means to attain the desired therapeutic profile with a reasonable expectation of success. As there is a reduction in the CMT it would implicitly have a reduction of the CST (being the center of the macula); additionally as the same ophthalmic eyedrop is being given for the recited treatment it would be expected to have the same amount of reduction in CST after treatment as addressed by the instant specification.
Response to Arguments:
Applicant's arguments are centered on the assertion the instant claims are nonobvious over Loftsson and the NHS and the assertion of case law which are addressed above.
Accordingly, the rejection stands.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15, 18-25 of U.S. Patent No. 12097209 in view of Genentech (Diabetic Macular Edema (DME) Fact Sheet) and Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Hutton (Oculis announces positive top line results from Phase 3 trial of OCS-01 drops for diabetic macular edema).
It is noted that Hutton falls under a 102(a)(1) date within a year of the instant priority date wherein the reference fall within the grace period and 102(b)(1) exceptions would apply.
The teachings of the patented claims in view of Genentech and Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop formulation that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The patented claims in view of Genentech and Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Hutton teaches that dexamethasone eyedrops (OCS-01) was given to diabetic macular edema patients six times daily for a six week loading phase and then 3 times daily for a six week maintenance phase; wherein there was a mean BCVA ETDRS score of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the dexamethasone eyedrop as suggested by Hutton and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success as it show a significant/unexpected improvement in the disease condition.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15, 18-25 of U.S. Patent No. 12097209 in view of Genentech (Diabetic Macular Edema (DME) Fact Sheet) and Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Oculis (Rethinking Ophthalmology –Oculis R&D Retina Day presentation 7/11/2023) or alternatively Oculis (Rethinking Ophthalmology – Investor Webcast 4/13/2023) or Oculis (Rethinking Ophthalmology –Jefferies Healthcare Conference 6/9/2023), or Tadayoni et al. (A 12-week Phase 2/3 Double-masked, Randomized, Multicenter Study of OCS-01 OPTIREACH Technology Topical Dexamethasone Eye Drops in Subjects with Diabetic Macular Edema (DME): Efficacy and Safety Findings).
It is noted that the secondary references to Oculis and Tadayoni et al. fall under 102(a)(1) dates within a year of the instant priority date wherein the references fall within the grace period and 102(b)(1) exceptions would apply.
Rejection:
The teachings of the patented claims in view of Genentech and Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop embodiment that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The patented claims in view of Genentech and Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Oculis (Rethinking Ophthalmology - Oculis R&D Retina Day) teaches that dexamethasone eyedrops 1.5%(15mg/ml, OCS-01) was given to diabetic macular edema patients six times daily for a six weeks and then 3 times daily for a six weeks (loading dose and then maintenance dose); wherein there was a mean BCVA ETDRS endpoint with statistically significant including scores of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%, Pages 7-8, 11-12, 15-20). Alternatively, the similar teachings are found in Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al. (Pages 3, 5, 11). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the taught dexamethasone eyedrop as suggested by Oculis (Rethinking Ophthalmology -Investor Webcast) or alternatively Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al.; and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success for show a significant/unexpected improvement in the disease condition.
Claims 1, 3, 6, 17-18, 20-23, 27-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18-19 of U.S. Patent No. 12090162 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops).
The patented claims are directed to the method of treating diabetic macular edema with the topical administration from a plastic container with an aqueous ophthalmic composition comprising
i) 1-4% w/v of dexamethasone;
ii) 5-25% w/v of γ-cyclodextrin;
iii) an antioxidation means (antioxidant) for preventing oxidation of dexamethasone and maintains a pH of 4.5-6
iv) water; wherein the composition comprises a microsuspension comprising solid complexes of dexamethasone and γ-cyclodextrin (has no preservative).
While the patented claims does not recite the exact claimed values for the components, they do embrace the claimed ranges wherein it would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize within the taught range and arrive at the claimed values as a means of attaining the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values.
The patented claims does not expressly teach the instant claimed dosing regimen, a poloxamer, a chelator, an electrolyte, the amount of antioxidant, the size of the solid dexamethasone/cyclodextrin complex, and usefulness for VEGF naïve patients; but does teach the treatment of diabetic macular edema with the aqueous dexamethasone/γ-cyclodextrin complex formulation.
Loftsson et al. teaches a dexamethasone/cyclodextrin/antioxidant aqueous formulation known for treating diabetic macular edema with the specific embodiment of
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0-0.2% of stabilizing agent, for example 0.1% of disodium edetate;
0-1% of electrolyte, for example 0.57% of sodium chloride;
0% to 0.6% of an additive to prevent the oxidation of the dexamethasone, for example between 0.1% and 0.5%, or between 0.2% and 0.4%, of an additive to prevent the oxidation of the corticosteroid, typically sodium thiosulfate;
that the preferred dosing of 1.5%w/v dexamethasone is 1-6 drops a day for a duration of at least 6, 7, 8, 9, 10, 11, or 12 weeks (Page 25 line 33-Page 26 line 23). That polymers like poloxamers are useful as stabilizers (Page 14 line 1-20, Page 15 line 1-20). That the solid complex of the drug and cyclodextrin has a D50 more particularly about 1um-about 10um as having it less than 10um prevents irritation of the eye (Page 9 line 1-13, Page 10 line 1-5), that the treatment is useful for patients with no or inadequate response to VEGF inhibitors including those with retinal thickening in the affected eye due to diabetic macular edema (VEGF inhibitor naïve, Page 27 line 13-20), and that the central macular thickness (CMT) can be significantly reduced after 12 weeks of treatment in a patient suffering from DME, such as more than 10% CMT as measured from baseline, and have improved pin hole visual acuity from baseline to at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME (Page 27 line 4-11), and the patient is a human patient (Page 27 line 21, Page 29-30, Page 35-36).
NHS (National Health Service) teaches that dexamethasone eye drops are known to be usually given at one eyedrop 4-6 times a day and once your symptoms are better the doctor may have you reduce the dose before stopping completely (Dosage, How long to use eye drops).
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have an initial dosing regimen and then lower the dosing regimen of the formulation, utilize excipients for a known dexamethasone/cyclodextrin/antioxidant formulation known for this treatment, a known size of the solid dexamethasone/cyclodextrin complex, and useful for a VEGF naïve subject as suggested by Loftsson et al. and NHS and produce the claimed invention; as it is prima facie obvious to dose dexamethasone in its known regimen as taught by Loftsson et al. and NHS (i.e. 1 drop 6x/day) and to reduce the dose as the symptoms improve as established by NHS within the known parameters described by Loftsson et al. (i.e. 1 drop 1-3x/day) for as long as needed to achieve the desired therapeutic outcome (i.e. 6 weeks or more (e.g. 2 weeks until symptoms improve and 6 weeks or more at reduced dose until desired therapeutic outcome is achieved) with known excipients/antioxidants in a known dexamethasone/cyclodextrin/antioxidant formulation known for this purpose in patients like VEGF naïve patients including those with retinal thickening in the affected eye due to diabetic macular edema, with a reasonable expectation of success absent evidence of criticality for the recited dose and duration. It is also prima facie obvious to formulate the solid drug/cyclodextrin complex in this known range as having it less than 10um prevents irritation of the eye which is desirable with a reasonable expectation of success.
While the exact claimed mean ETDRS letters of improvement or central subfield thickness (CST) are not recited, the reduction of the central macular thickness (CMT) is embraced by the taught range (reduced after 12 weeks of treatment with the recited formulation in a patient suffering from DME by at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME) where it would be prima facie obvious to optimize the amount of improvement by the amount of treatment as a means to attain the desired therapeutic profile with a reasonable expectation of success. As there is a reduction in the CMT it would implicitly have a reduction of the CST (being the center of the macula); additionally as the same ophthalmic eyedrop is being given for the recited treatment it would be expected to have the same amount of reduction in CST after treatment as addressed by the instant specification.
Response to Arguments:
Applicant's arguments are centered on the assertion the instant claims are nonobvious over Loftsson and the NHS and the assertion of case law which are addressed above.
Accordingly, the rejection stands.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18-19 of U.S. Patent No. 12090162 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Hutton (Oculis announces positive top line results from Phase 3 trial of OCS-01 drops for diabetic macular edema).
It is noted that Hutton falls under a 102(a)(1) date within a year of the instant priority date wherein the reference fall within the grace period and 102(b)(1) exceptions would apply.
The teachings of the patented claims in view of Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop formulation that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The patented claims in view of Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Hutton teaches that dexamethasone eyedrops (OCS-01) was given to diabetic macular edema patients six times daily for a six week loading phase and then 3 times daily for a six week maintenance phase; wherein there was a mean BCVA ETDRS score of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the dexamethasone eyedrop as suggested by Hutton and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success as it show a significant/unexpected improvement in the disease condition.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18-19 of U.S. Patent No. 12090162 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Oculis (Rethinking Ophthalmology –Oculis R&D Retina Day presentation 7/11/2023) or alternatively Oculis (Rethinking Ophthalmology – Investor Webcast 4/13/2023) or Oculis (Rethinking Ophthalmology –Jefferies Healthcare Conference 6/9/2023), or Tadayoni et al. (A 12-week Phase 2/3 Double-masked, Randomized, Multicenter Study of OCS-01 OPTIREACH Technology Topical Dexamethasone Eye Drops in Subjects with Diabetic Macular Edema (DME): Efficacy and Safety Findings).
It is noted that the secondary references to Oculis and Tadayoni et al. fall under 102(a)(1) dates within a year of the instant priority date wherein the references fall within the grace period and 102(b)(1) exceptions would apply.
Rejection:
The teachings of the patented claims in view of Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop embodiment that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The patented claims in view of Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Oculis (Rethinking Ophthalmology - Oculis R&D Retina Day) teaches that dexamethasone eyedrops 1.5%(15mg/ml, OCS-01) was given to diabetic macular edema patients six times daily for a six weeks and then 3 times daily for a six weeks (loading dose and then maintenance dose); wherein there was a mean BCVA ETDRS endpoint with statistically significant including scores of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%, Pages 7-8, 11-12, 15-20). Alternatively, the similar teachings are found in Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al. (Pages 3, 5, 11). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the taught dexamethasone eyedrop as suggested by Oculis (Rethinking Ophthalmology -Investor Webcast) or alternatively Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al.; and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success for show a significant/unexpected improvement in the disease condition.
Claims 1, 3, 6, 17-18, 20-23, 27-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 12090162 in view of Genentech (Diabetic Macular Edema (DME) Fact Sheet) and Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops).
The patented claim 1 is directed to the method of treating diabetic retinopathy with the topical administration from a plastic container with an aqueous ophthalmic composition comprising
i) 1-4% w/v of dexamethasone;
ii) 5-25% w/v of γ-cyclodextrin;
iii) an antioxidation means (antioxidant) for preventing oxidation of dexamethasone and maintains a pH of 4.5-6
iv) water; wherein the composition comprises a microsuspension comprising solid complexes of dexamethasone and γ-cyclodextrin (has no preservative).
Its dependent claims recite the size of the solid complexes to have a D50 of about 1-10um, the antioxidant to be sodium thiosulfate, poloxamer at 2.2-2.8%w/v, disodium edetate from 0-0.2% and at 0.1%, the electrolyte to be sodium chloride and at 0.57%w/v, and the subject to be VEGF inhibitor naïve.
While the patented claims does not recite the exact claimed values for the dexamethasone and cyclodextrin, they do embrace the claimed ranges wherein it would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize within the taught range and arrive at the claimed values as a means of attaining the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values.
The patented claims does not expressly teach the instant claimed dosing regimen for diabetic macular edema, a poloxamer, the amount of antioxidant, or the amount of a chelator, but does teach the treatment of diabetic retinopathy with the aqueous dexamethasone/γ-cyclodextrin complex formulation.
Genentech teaches that diabetic retinopathy that worsens can lead to diabetic macular edema, and that diabetic macular edema can occur at any stage of diabetic retinopathy although more likely as the disease progresses (paragraph 1-3).
Loftsson et al. teaches a dexamethasone/cyclodextrin/antioxidant aqueous formulation known for treating diabetic macular edema with the specific embodiment of
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0-0.2% of stabilizing agent, for example 0.1% of disodium edetate;
0-1% of electrolyte, for example 0.57% of sodium chloride;
0% to 0.6% of an additive to prevent the oxidation of the dexamethasone, for example between 0.1% and 0.5%, or between 0.2% and 0.4%, of an additive to prevent the oxidation of the corticosteroid, typically sodium thiosulfate;
that the preferred dosing of 1.5%w/v dexamethasone is 1-6 drops a day for a duration of at least 6, 7, 8, 9, 10, 11, or 12 weeks (Page 25 line 33-Page 26 line 23). That polymers like poloxamers are useful as stabilizers (Page 14 line 1-20, Page 15 line 1-20). That the solid complex of the drug and cyclodextrin has a D50 more particularly about 1um-about 10um as having it less than 10um prevents irritation of the eye (Page 9 line 1-13, Page 10 line 1-5), that the treatment is useful for patients with no or inadequate response to VEGF inhibitors including those with retinal thickening in the affected eye due to diabetic macular edema (VEGF inhibitor naïve, Page 27 line 13-20), and that the central macular thickness (CMT) can be significantly reduced after 12 weeks of treatment in a patient suffering from DME, from baseline to at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME (Page 27 line 4-11), and the patient is a human patient (Page 27 line 21, Page 29-30, Page 35-36).
NHS (National Health Service) teaches that dexamethasone eye drops are known to be usually given at one eyedrop 4-6 times a day and once your symptoms are better the doctor may have you reduce the dose before stopping completely (Dosage, How long to use eye drops).
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat diabetic macular edema with an initial dosing regimen and then lower the dosing regimen of the formulation and utilize excipients for a known dexamethasone/cyclodextrin/antioxidant formulation useful for this treatment and useful for a VEGF naïve subject as suggested by Genentech and Loftsson et al. and NHS and produce the claimed invention; as it is prima facie obvious to not only treat diabetic retinopathy but its known complication of diabetic macular edema as addressed by Genentech with the taught dexamethasone/cyclodextrin/antioxidant formulation in its known regimen as taught by Loftsson et al. and NHS (i.e. 1 drop 6x/day) and to reduce the dose as the symptoms improve as established by NHS within the known parameters described by Loftsson et al. (i.e. 1 drop 1-3x/day) for as long as needed to achieve the desired therapeutic outcome (i.e. 6 weeks or more (e.g. 2 weeks until symptoms improve and 6 weeks or more at reduced dose until desired therapeutic outcome is achieved) with known excipients/antioxidants in a known dexamethasone/cyclodextrin/antioxidant formulation useful for this purpose in patients like VEGF naïve patients including those with retinal thickening in the affected eye due to diabetic macular edema, with a reasonable expectation of success absent evidence of criticality for the recited dose and duration.
While the exact claimed mean ETDRS letters of improvement or central subfield thickness (CST) are not recited, the reduction of the central macular thickness (CMT) is embraced by the taught range (reduced after 12 weeks of treatment with the recited formulation in a patient suffering from DME by at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME) where it would be prima facie obvious to optimize the amount of improvement by the amount of treatment as a means to attain the desired therapeutic profile with a reasonable expectation of success. As there is a reduction in the CMT it would implicitly have a reduction of the CST (being the center of the macula); additionally as the same ophthalmic eyedrop is being given for the recited treatment it would be expected to have the same amount of reduction in CST after treatment as addressed by the instant specification.
Response to Arguments:
Applicant's arguments are centered on the assertion the instant claims are nonobvious over Loftsson and the NHS and the assertion of case law which are addressed above.
Accordingly, the rejection stands.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 12090162 in view of Genentech (Diabetic Macular Edema (DME) Fact Sheet) and Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Hutton (Oculis announces positive top line results from Phase 3 trial of OCS-01 drops for diabetic macular edema).
It is noted that Hutton falls under a 102(a)(1) date within a year of the instant priority date wherein the reference fall within the grace period and 102(b)(1) exceptions would apply.
The teachings of the patented claims in view of Genentech and Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop formulation that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The patented claims in view of Genentech and Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Hutton teaches that dexamethasone eyedrops (OCS-01) was given to diabetic macular edema patients six times daily for a six week loading phase and then 3 times daily for a six week maintenance phase; wherein there was a mean BCVA ETDRS score of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the dexamethasone eyedrop as suggested by Hutton and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success as it show a significant/unexpected improvement in the disease condition.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 12090162 in view of Genentech (Diabetic Macular Edema (DME) Fact Sheet) and Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Oculis (Rethinking Ophthalmology –Oculis R&D Retina Day presentation 7/11/2023) or alternatively Oculis (Rethinking Ophthalmology – Investor Webcast 4/13/2023) or Oculis (Rethinking Ophthalmology –Jefferies Healthcare Conference 6/9/2023), or Tadayoni et al. (A 12-week Phase 2/3 Double-masked, Randomized, Multicenter Study of OCS-01 OPTIREACH Technology Topical Dexamethasone Eye Drops in Subjects with Diabetic Macular Edema (DME): Efficacy and Safety Findings).
It is noted that the secondary references to Oculis and Tadayoni et al. fall under 102(a)(1) dates within a year of the instant priority date wherein the references fall within the grace period and 102(b)(1) exceptions would apply.
Rejection:
The teachings of the patented claims in view of Genentech and Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop embodiment that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The patented claims in view of Genentech and Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Oculis (Rethinking Ophthalmology - Oculis R&D Retina Day) teaches that dexamethasone eyedrops 1.5%(15mg/ml, OCS-01) was given to diabetic macular edema patients six times daily for a six weeks and then 3 times daily for a six weeks (loading dose and then maintenance dose); wherein there was a mean BCVA ETDRS endpoint with statistically significant including scores of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%, Pages 7-8, 11-12, 15-20). Alternatively, the similar teachings are found in Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al. (Pages 3, 5, 11). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the taught dexamethasone eyedrop as suggested by Oculis (Rethinking Ophthalmology -Investor Webcast) or alternatively Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al.; and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success for show a significant/unexpected improvement in the disease condition.
Claims 1, 3, 6, 17-18, 20-23, 27-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18-19 and 27-28 of U.S. Patent No. 12383565 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops).
The patented claims are directed to the method of treating diabetic macular edema with the topical administration from a plastic container with an aqueous ophthalmic composition comprising
i) 1-4% w/v of dexamethasone;
ii) 5-25% w/v of γ-cyclodextrin;
iii) 0.1-0.5% w/v of sodium thiosulfate; and,
iv) water; wherein the composition comprises a microsuspension comprising solid complexes of dexamethasone and γ-cyclodextrin (has no preservative), and a pH of 4.5-6.
While the patented claims do not recite the exact claimed values for the components, they do embrace the claimed ranges wherein it would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize within the taught range and arrive at the claimed values as a means of attaining the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values.
The patented claims does not expressly teach the instant claimed dosing regimen, poloxamer 407, disodium edetate, sodium chloride, the size of the solid dexamethasone/cyclodextrin complex, and usefulness for VEGF naïve patients; but does teach the treatment of diabetic macular edema with the aqueous dexamethasone/γ-cyclodextrin complex formulation.
Loftsson et al. teaches a dexamethasone/cyclodextrin/antioxidant aqueous formulation known for treating diabetic macular edema with the specific embodiment of
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0-0.2% of stabilizing agent, for example 0.1% of disodium edetate;
0-1% of electrolyte, for example 0.57% of sodium chloride;
0% to 0.6% of an additive to prevent the oxidation of the dexamethasone like sodium thiosulfate, for example between 0.1% and 0.5%, or between 0.2% and 0.4%;
that the preferred dosing of 1.5%w/v dexamethasone is 1-6 drops a day for a duration of at least 6, 7, 8, 9, 10, 11, or 12 weeks (Page 25 line 33-Page 26 line 23). That polymers like poloxamers are useful as stabilizers (Page 14 line 1-20, Page 15 line 1-20). That the solid complex of the drug and cyclodextrin has a D50 more particularly about 1um-about 10um as having it less than 10um prevents irritation of the eye (Page 9 line 1-13, Page 10 line 1-5), that the treatment is useful for patients with no or inadequate response to VEGF inhibitors including those with retinal thickening in the affected eye due to diabetic macular edema (VEGF inhibitor naïve, Page 27 line 13-20), and that the central macular thickness (CMT) can be significantly reduced after 12 weeks of treatment in a patient suffering from DME, from baseline to at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME (Page 27 line 4-11), and the patient is a human patient (Page 27 line 21, Page 29-30, Page 35-36).
NHS (National Health Service) teaches that dexamethasone eye drops are known to be usually given at one eyedrop 4-6 times a day and once your symptoms are better the doctor may have you reduce the dose before stopping completely (Dosage, How long to use eye drops).
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have an initial dosing regimen and then lower the dosing regimen of the formulation, a known pH of the formulation, a known size of the solid dexamethasone/cyclodextrin complex, that the electrolyte can be sodium chloride, and useful for a VEGF naïve subject as suggested by Loftsson et al. and NHS and produce the claimed invention; as it is prima facie obvious to dose dexamethasone in its known regimen as taught by Loftsson et al. and NHS (i.e. 1 drop 6x/day) and to reduce the dose as the symptoms improve as established by NHS within the known parameters described by Loftsson et al. (i.e. 1 drop 1-3x/day) for as long as needed to achieve the desired therapeutic outcome (i.e. 6 weeks or more (e.g. 2 weeks until symptoms improve and 6 weeks or more at reduced dose until desired therapeutic outcome is achieved) in patients like VEGF naïve patients including those with retinal thickening in the affected eye due to diabetic macular edema, with a reasonable expectation of success absent evidence of criticality for the recited dose and duration. It is also prima facie obvious to optimize the pH of the formulation within its known range (4.5-6) and arrive at the recited values as a means of attain the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values; and prima facie obvious to utilize a known electrolyte like sodium chloride for the formulation with a reasonable expectation of success.
While the patented claims do not expressly recite the D50 of the drug/cyclodextrin complex, the prior art teaches that the solid complex of the drug/cyclodextrin can have a D50 of about 1um-about 10um wherein it is prima facie obvious to formulate the solid drug/cyclodextrin complex in this known range as having it less than 10um prevents irritation of the eye which is desirable with a reasonable expectation of success.
While the exact claimed mean ETDRS letters of improvement or central subfield thickness (CST) are not recited, the reduction of the central macular thickness (CMT) is embraced by the taught range (reduced after 12 weeks of treatment with the recited formulation in a patient suffering from DME by at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME) where it would be prima facie obvious to optimize the amount of improvement by the amount of treatment as a means to attain the desired therapeutic profile with a reasonable expectation of success. As there is a reduction in the CMT it would implicitly have a reduction of the CST (being the center of the macula); additionally as the same ophthalmic eyedrop is being given for the recited treatment it would be expected to have the same amount of reduction in CST after treatment as addressed by the instant specification.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18-19 and 27-28 of U.S. Patent No. 12383565 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Hutton (Oculis announces positive top line results from Phase 3 trial of OCS-01 drops for diabetic macular edema).
It is noted that Hutton falls under a 102(a)(1) date within a year of the instant priority date wherein the reference fall within the grace period and 102(b)(1) exceptions would apply.
The teachings of the patented claims in view of Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop formulation that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The patented claims in view of Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Hutton teaches that dexamethasone eyedrops (OCS-01) was given to diabetic macular edema patients six times daily for a six week loading phase and then 3 times daily for a six week maintenance phase; wherein there was a mean BCVA ETDRS score of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the dexamethasone eyedrop as suggested by Hutton and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success as it show a significant/unexpected improvement in the disease condition.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18-19 and 27-28 of U.S. Patent No. 12383565 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Oculis (Rethinking Ophthalmology –Oculis R&D Retina Day presentation 7/11/2023) or alternatively Oculis (Rethinking Ophthalmology – Investor Webcast 4/13/2023) or Oculis (Rethinking Ophthalmology –Jefferies Healthcare Conference 6/9/2023), or Tadayoni et al. (A 12-week Phase 2/3 Double-masked, Randomized, Multicenter Study of OCS-01 OPTIREACH Technology Topical Dexamethasone Eye Drops in Subjects with Diabetic Macular Edema (DME): Efficacy and Safety Findings).
It is noted that the secondary references to Oculis and Tadayoni et al. fall under 102(a)(1) dates within a year of the instant priority date wherein the references fall within the grace period and 102(b)(1) exceptions would apply.
Rejection:
The teachings of the patented claims in view of Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop embodiment that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The patented claims in view of Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Oculis (Rethinking Ophthalmology - Oculis R&D Retina Day) teaches that dexamethasone eyedrops 1.5%(15mg/ml, OCS-01) was given to diabetic macular edema patients six times daily for a six weeks and then 3 times daily for a six weeks (loading dose and then maintenance dose); wherein there was a mean BCVA ETDRS endpoint with statistically significant including scores of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%, Pages 7-8, 11-12, 15-20). Alternatively, the similar teachings are found in Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al. (Pages 3, 5, 11). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the taught dexamethasone eyedrop as suggested by Oculis (Rethinking Ophthalmology -Investor Webcast) or alternatively Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al.; and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success for show a significant/unexpected improvement in the disease condition.
Claims 1, 3, 6, 17-18, 20-23, 27-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 and 20-26 and 29 of U.S. Patent No. 12383565 (previously copending application 18/893805) in view of Genentech (Diabetic Macular Edema (DME) Fact Sheet) and Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops).
The patented independent claims are directed to the method of treating diabetic retinopathy with the topical administration from a container with an aqueous ophthalmic composition comprising
i) 1-4% w/v of dexamethasone;
ii) 5-25% w/v of γ-cyclodextrin;
iii) 0.1-0.5% sodium thiosulfate and maintains a pH of 4.5-6
iv) water; wherein the composition comprises a microsuspension comprising solid complexes of dexamethasone and γ-cyclodextrin (has no preservative).
Its dependent claims recite the size of the solid complexes to have a D50 of about 1-10um, poloxamer at 2.2-2.8%w/v, disodium edetate from 0-0.2% and at 0.1%, an electrolyte at 0-1% like sodium chloride, and the subject to be VEGF inhibitor naïve.
While the patented claims does not recite the exact claimed values for the dexamethasone and cyclodextrin and sodium thiosulfate, it is embraced by the patented ranges wherein it would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize within the taught range and arrive at the claimed values as a means of attaining the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values.
The patented claims does not expressly teach the instant claimed dosing regimen for diabetic macular edema, type of poloxamer, the amount of a chelator or sodium chloride but does teach the treatment of diabetic retinopathy with the aqueous dexamethasone/γ-cyclodextrin complex formulation.
Genentech teaches that diabetic retinopathy that worsens can lead to diabetic macular edema, and that diabetic macular edema can occur at any stage of diabetic retinopathy although more likely as the disease progresses (paragraph 1-3).
Loftsson et al. teaches a dexamethasone/cyclodextrin/antioxidant aqueous formulation known for treating diabetic macular edema with the specific embodiment of
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0-0.2% of stabilizing agent, for example 0.1% of disodium edetate;
0-1% of electrolyte, for example 0.57% of sodium chloride;
0% to 0.6% of an additive to prevent the oxidation of the dexamethasone, for example between 0.1% and 0.5%, or between 0.2% and 0.4%, of an additive to prevent the oxidation of the corticosteroid, typically sodium thiosulfate;
that the preferred dosing of 1.5%w/v dexamethasone is 1-6 drops a day for a duration of at least 6, 7, 8, 9, 10, 11, or 12 weeks (Page 25 line 33-Page 26 line 23). That polymers like poloxamers are useful as stabilizers (Page 14 line 1-20, Page 15 line 1-20). That the solid complex of the drug and cyclodextrin has a D50 more particularly about 1um-about 10um as having it less than 10um prevents irritation of the eye (Page 9 line 1-13, Page 10 line 1-5), that the treatment is useful for patients with no or inadequate response to VEGF inhibitors including those with retinal thickening in the affected eye due to diabetic macular edema (VEGF inhibitor naïve, Page 27 line 13-20), and that the central macular thickness (CMT) can be significantly reduced after 12 weeks of treatment in a patient suffering from DME, from baseline to at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME (Page 27 line 4-11), and the patient is a human patient (Page 27 line 21, Page 29-30, Page 35-36).
NHS (National Health Service) teaches that dexamethasone eye drops are known to be usually given at one eyedrop 4-6 times a day and once your symptoms are better the doctor may have you reduce the dose before stopping completely (Dosage, How long to use eye drops).
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat diabetic macular edema with an initial dosing regimen and then lower the dosing regimen of the formulation and utilize excipients for a known dexamethasone/cyclodextrin/antioxidant formulation useful for this treatment and useful for a VEGF naïve subject as suggested by Genentech and Loftsson et al. and NHS and produce the claimed invention; as it is prima facie obvious to not only treat diabetic retinopathy but its known complication of diabetic macular edema as addressed by Genentech with the taught dexamethasone/cyclodextrin/antioxidant formulation in its known regimen as taught by Loftsson et al. and NHS (i.e. 1 drop 6x/day) and to reduce the dose as the symptoms improve as established by NHS within the known parameters described by Loftsson et al. (i.e. 1 drop 1-3x/day) for as long as needed to achieve the desired therapeutic outcome (i.e. 6 weeks or more (e.g. 2 weeks until symptoms improve and 6 weeks or more at reduced dose until desired therapeutic outcome is achieved) with known excipients/antioxidants in a known dexamethasone/cyclodextrin/antioxidant formulation useful for this purpose in patients like VEGF naïve patients including those with retinal thickening in the affected eye due to diabetic macular edema, with a reasonable expectation of success absent evidence of criticality for the recited dose and duration.
While the exact claimed mean ETDRS letters of improvement or central subfield thickness (CST) are not recited, the reduction of the central macular thickness (CMT) is embraced by the taught range (reduced after 12 weeks of treatment with the recited formulation in a patient suffering from DME by at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME) where it would be prima facie obvious to optimize the amount of improvement by the amount of treatment as a means to attain the desired therapeutic profile with a reasonable expectation of success. As there is a reduction in the CMT it would implicitly have a reduction of the CST (being the center of the macula); additionally as the same ophthalmic eyedrop is being given for the recited treatment it would be expected to have the same amount of reduction in CST after treatment as addressed by the instant specification.
Response to Arguments:
Applicant's arguments are centered on the assertion the instant claims are nonobvious over Loftsson and the NHS and the assertion of case law which are addressed above.
Accordingly, the rejection stands.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable claims 1-17 and 20-26 and 29 of U.S. Patent No. 12383565 in view of Genentech (Diabetic Macular Edema (DME) Fact Sheet) and Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Hutton (Oculis announces positive top line results from Phase 3 trial of OCS-01 drops for diabetic macular edema).
It is noted that Hutton falls under a 102(a)(1) date within a year of the instant priority date wherein the reference fall within the grace period and 102(b)(1) exceptions would apply.
The teachings of the patented claims in view of Genentech and Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop formulation that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The patented claims in view of Genentech and Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Hutton teaches that dexamethasone eyedrops (OCS-01) was given to diabetic macular edema patients six times daily for a six week loading phase and then 3 times daily for a six week maintenance phase; wherein there was a mean BCVA ETDRS score of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the dexamethasone eyedrop as suggested by Hutton and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success as it show a significant/unexpected improvement in the disease condition.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable claims 1-17 and 20-26 and 29 of U.S. Patent No. 12383565 in view of Genentech (Diabetic Macular Edema (DME) Fact Sheet) and Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Oculis (Rethinking Ophthalmology –Oculis R&D Retina Day presentation 7/11/2023) or alternatively Oculis (Rethinking Ophthalmology – Investor Webcast 4/13/2023) or Oculis (Rethinking Ophthalmology –Jefferies Healthcare Conference 6/9/2023), or Tadayoni et al. (A 12-week Phase 2/3 Double-masked, Randomized, Multicenter Study of OCS-01 OPTIREACH Technology Topical Dexamethasone Eye Drops in Subjects with Diabetic Macular Edema (DME): Efficacy and Safety Findings).
It is noted that the secondary references to Oculis and Tadayoni et al. fall under 102(a)(1) dates within a year of the instant priority date wherein the references fall within the grace period and 102(b)(1) exceptions would apply.
Rejection:
The teachings of the patented claims in view of Genentech and Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop embodiment that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The patented claims in view of Genentech and Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Oculis (Rethinking Ophthalmology - Oculis R&D Retina Day) teaches that dexamethasone eyedrops 1.5%(15mg/ml, OCS-01) was given to diabetic macular edema patients six times daily for a six weeks and then 3 times daily for a six weeks (loading dose and then maintenance dose); wherein there was a mean BCVA ETDRS endpoint with statistically significant including scores of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%, Pages 7-8, 11-12, 15-20). Alternatively, the similar teachings are found in Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al. (Pages 3, 5, 11). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the taught dexamethasone eyedrop as suggested by Oculis (Rethinking Ophthalmology -Investor Webcast) or alternatively Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al.; and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success for show a significant/unexpected improvement in the disease condition.
Claims 1, 3, 6, 17-18, 20-23, 27-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12397000 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops).
The patented independent claims are directed to an aqueous composition in a container such as a plastic container comprising
i) 1-4% w/v of dexamethasone;
ii) 5-25% w/v of γ-cyclodextrin;
iii) 0.1-0.5% w/v of sodium thiosulfate; and,
iv) water; wherein the composition comprises a microsuspension comprising solid complexes of dexamethasone and γ-cyclodextrin (has no preservative), and a pH of 4.5-6. The dependent claims are to specific concentrations of dexamethasone and cyclodextrin and sodium thiosulfate, types and concentration of poloxamer, 0.1% electrolyte like sodium chloride, the size of the dexamethasone/cyclodextrin complex. Dependent claims are directed to particular concentrations of dexamethasone and cyclodextrin and sodium thiosulfate, types of poloxamer like 407 and its concentration, 0-0.2% and 0.1% disodium edetate, 0-1% electrolyte like sodium chloride, and microparticle size.
While the patented claims do not recite the exact claimed values for the components, they do embrace the claimed ranges wherein it would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize within the taught range and arrive at the claimed values as a means of attaining the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values.
The patented claims does not expressly teach the instant claimed method of treating diabetic macular edema, the dosing regimen, poloxamer 407, disodium edetate, sodium chloride, the size of the solid dexamethasone/cyclodextrin complex, and usefulness for VEGF naïve patients; but does teach an ophthalmic composition comprising the dexamethasone, cyclodextrin, sodium thiosulfate, and water with a pH of 4.5-6.
Loftsson et al. teaches a dexamethasone/cyclodextrin/antioxidant aqueous formulation known for treating diabetic macular edema with the specific embodiment of
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0-0.2% of stabilizing agent, for example 0.1% of disodium edetate;
0-1% of electrolyte, for example 0.57% of sodium chloride;
0% to 0.6% of an additive to prevent the oxidation of the dexamethasone like sodium thiosulfate, for example between 0.1% and 0.5%, or between 0.2% and 0.4%;
that the preferred dosing of 1.5%w/v dexamethasone is 1-6 drops a day for a duration of at least 6, 7, 8, 9, 10, 11, or 12 weeks (Page 25 line 33-Page 26 line 23). That polymers like poloxamers are useful as stabilizers (Page 14 line 1-20, Page 15 line 1-20). That the solid complex of the drug and cyclodextrin has a D50 more particularly about 1um-about 10um as having it less than 10um prevents irritation of the eye (Page 9 line 1-13, Page 10 line 1-5), that the treatment is useful for patients with no or inadequate response to VEGF inhibitors including those with retinal thickening in the affected eye due to diabetic macular edema (VEGF inhibitor naïve, Page 27 line 13-20), and that the central macular thickness (CMT) can be significantly reduced after 12 weeks of treatment in a patient suffering from DME, from baseline to at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME (Page 27 line 4-11), and the patient is a human patient (Page 27 line 21, Page 29-30, Page 35-36).
NHS (National Health Service) teaches that dexamethasone eye drops are known to be usually given at one eyedrop 4-6 times a day and once your symptoms are better the doctor may have you reduce the dose before stopping completely (Dosage, How long to use eye drops).
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the dexamethasone composition to treat diabetic macular edema in an initial dosing regimen and then lower the dosing regimen of the formulation, a known pH of the formulation, a known size of the solid dexamethasone/cyclodextrin complex, excipients like sodium edetate and poloxamer 407 and sodium chloride, and useful for a VEGF naïve subject as suggested by Loftsson et al. and NHS and produce the claimed invention; as it is prima facie obvious to use and ophthalmic dexamethasone composition for its known treatment and dose the dexamethasone in its known regimen as taught by Loftsson et al. and NHS (i.e. 1 drop 6x/day) and to reduce the dose as the symptoms improve as established by NHS within the known parameters described by Loftsson et al. (i.e. 1 drop 1-3x/day) for as long as needed to achieve the desired therapeutic outcome (i.e. 6 weeks or more (e.g. 2 weeks until symptoms improve and 6 weeks or more at reduced dose until desired therapeutic outcome is achieved) in patients like VEGF naïve patients including those with retinal thickening in the affected eye due to diabetic macular edema, with a reasonable expectation of success absent evidence of criticality for the recited dose and duration. It is also prima facie obvious to incorporate excipients that are known to be in a dexamethasone ophthalmic composition as a means of attain the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values.
While the patented claims do not expressly recite the D50 of the drug/cyclodextrin complex, the prior art teaches that the solid complex of the drug/cyclodextrin can have a D50 of about 1um-about 10um wherein it is prima facie obvious to formulate the solid drug/cyclodextrin complex in this known range as having it less than 10um prevents irritation of the eye which is desirable with a reasonable expectation of success.
While the exact claimed mean ETDRS letters of improvement or central subfield thickness (CST) are not recited, the reduction of the central macular thickness (CMT) is embraced by the taught range (reduced after 12 weeks of treatment with the recited formulation in a patient suffering from DME by at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME) where it would be prima facie obvious to optimize the amount of improvement by the amount of treatment as a means to attain the desired therapeutic profile with a reasonable expectation of success. As there is a reduction in the CMT it would implicitly have a reduction of the CST (being the center of the macula); additionally as the same ophthalmic eyedrop is being given for the recited treatment it would be expected to have the same amount of reduction in CST after treatment as addressed by the instant specification.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12397000 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Hutton (Oculis announces positive top line results from Phase 3 trial of OCS-01 drops for diabetic macular edema).
It is noted that Hutton falls under a 102(a)(1) date within a year of the instant priority date wherein the reference fall within the grace period and 102(b)(1) exceptions would apply.
The teachings of the patented claims in view of Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop formulation that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The patented claims in view of Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Hutton teaches that dexamethasone eyedrops (OCS-01) was given to diabetic macular edema patients six times daily for a six week loading phase and then 3 times daily for a six week maintenance phase; wherein there was a mean BCVA ETDRS score of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the dexamethasone eyedrop as suggested by Hutton and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success as it show a significant/unexpected improvement in the disease condition.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12397000 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Oculis (Rethinking Ophthalmology –Oculis R&D Retina Day presentation 7/11/2023) or alternatively Oculis (Rethinking Ophthalmology – Investor Webcast 4/13/2023) or Oculis (Rethinking Ophthalmology –Jefferies Healthcare Conference 6/9/2023), or Tadayoni et al. (A 12-week Phase 2/3 Double-masked, Randomized, Multicenter Study of OCS-01 OPTIREACH Technology Topical Dexamethasone Eye Drops in Subjects with Diabetic Macular Edema (DME): Efficacy and Safety Findings).
It is noted that the secondary references to Oculis and Tadayoni et al. fall under 102(a)(1) dates within a year of the instant priority date wherein the references fall within the grace period and 102(b)(1) exceptions would apply.
Rejection:
The teachings of the patented claims in view of Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop embodiment that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The patented claims in view of Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Oculis (Rethinking Ophthalmology - Oculis R&D Retina Day) teaches that dexamethasone eyedrops 1.5%(15mg/ml, OCS-01) was given to diabetic macular edema patients six times daily for a six weeks and then 3 times daily for a six weeks (loading dose and then maintenance dose); wherein there was a mean BCVA ETDRS endpoint with statistically significant including scores of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%, Pages 7-8, 11-12, 15-20). Alternatively, the similar teachings are found in Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al. (Pages 3, 5, 11). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the taught dexamethasone eyedrop as suggested by Oculis (Rethinking Ophthalmology -Investor Webcast) or alternatively Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al.; and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success for show a significant/unexpected improvement in the disease condition.
Claims 1, 3, 6, 17-18, 20-23, 27-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 12397002 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops).
The patented claims are directed to an aqueous composition in a container comprising
i) 1-4% w/v of dexamethasone;
ii) 5-25% w/v of γ-cyclodextrin;
iii) 0.1-0.5% w/v of antioxidation means (antioxidant); and,
iv) water; wherein the composition comprises a microsuspension comprising solid complexes of dexamethasone and γ-cyclodextrin (has no preservative), and a pH of 4.5-6. The dependent claims are to specific concentrations of dexamethasone and cyclodextrin, the inclusion of sodium thiosulfate as the antioxidant, types and concentration of poloxamer, 0.1% electrolyte like sodium chloride, the size of the dexamethasone/cyclodextrin complex, and the container to be plastic.
While the patented claims do not recite the exact claimed values for the components like dexamethasone and cyclodextrin, they do embrace the claimed ranges wherein it would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize within the taught range and arrive at the claimed values as a means of attaining the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values.
The patented claims does not expressly teach the instant claimed method of treating diabetic macular edema, the dosing regimen, poloxamer 407, disodium edetate, sodium chloride, the size of the solid dexamethasone/cyclodextrin complex, the amount of antioxidant like sodium thiosulfate, and usefulness for VEGF naïve patients; but does teach an ophthalmic composition comprising the dexamethasone, cyclodextrin, an antioxidant, and water with a pH of 4.5-6.
Loftsson et al. teaches a dexamethasone/cyclodextrin/antioxidant aqueous formulation known for treating diabetic macular edema with the specific embodiment of
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0-0.2% of stabilizing agent, for example 0.1% of disodium edetate;
0-1% of electrolyte, for example 0.57% of sodium chloride;
0% to 0.6% of an additive to prevent the oxidation of the dexamethasone like sodium thiosulfate, for example between 0.1% and 0.5%, or between 0.2% and 0.4%;
that the preferred dosing of 1.5%w/v dexamethasone is 1-6 drops a day for a duration of at least 6, 7, 8, 9, 10, 11, or 12 weeks (Page 25 line 33-Page 26 line 23). That polymers like poloxamers are useful as stabilizers (Page 14 line 1-20, Page 15 line 1-20). That the solid complex of the drug and cyclodextrin has a D50 more particularly about 1um-about 10um as having it less than 10um prevents irritation of the eye (Page 9 line 1-13, Page 10 line 1-5), that the treatment is useful for patients with no or inadequate response to VEGF inhibitors including those with retinal thickening in the affected eye due to diabetic macular edema (VEGF inhibitor naïve, Page 27 line 13-20), and that the central macular thickness (CMT) can be significantly reduced after 12 weeks of treatment in a patient suffering from DME, from baseline to at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME (Page 27 line 4-11), and the patient is a human patient (Page 27 line 21, Page 29-30, Page 35-36).
NHS (National Health Service) teaches that dexamethasone eye drops are known to be usually given at one eyedrop 4-6 times a day and once your symptoms are better the doctor may have you reduce the dose before stopping completely (Dosage, How long to use eye drops).
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the dexamethasone composition to treat diabetic macular edema in an initial dosing regimen and then lower the dosing regimen of the formulation, a known pH of the formulation, a known size of the solid dexamethasone/cyclodextrin complex, excipients like sodium edetate and poloxamer 407 and sodium chloride, and useful for a VEGF naïve subject as suggested by Loftsson et al. and NHS and produce the claimed invention; as it is prima facie obvious to use and ophthalmic dexamethasone composition for its known treatment and dose the dexamethasone in its known regimen as taught by Loftsson et al. and NHS (i.e. 1 drop 6x/day) and to reduce the dose as the symptoms improve as established by NHS within the known parameters described by Loftsson et al. (i.e. 1 drop 1-3x/day) for as long as needed to achieve the desired therapeutic outcome (i.e. 6 weeks or more (e.g. 2 weeks until symptoms improve and 6 weeks or more at reduced dose until desired therapeutic outcome is achieved) in patients like VEGF naïve patients including those with retinal thickening in the affected eye due to diabetic macular edema, with a reasonable expectation of success absent evidence of criticality for the recited dose and duration. It is also prima facie obvious to incorporate excipients that are known to be in a dexamethasone ophthalmic composition as a means of attain the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values.
While the patented claims do not expressly recite the D50 of the drug/cyclodextrin complex, the prior art teaches that the solid complex of the drug/cyclodextrin can have a D50 of about 1um-about 10um wherein it is prima facie obvious to formulate the solid drug/cyclodextrin complex in this known range as having it less than 10um prevents irritation of the eye which is desirable with a reasonable expectation of success.
While the exact claimed mean ETDRS letters of improvement or central subfield thickness (CST) are not recited, the reduction of the central macular thickness (CMT) is embraced by the taught range (reduced after 12 weeks of treatment with the recited formulation in a patient suffering from DME by at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME) where it would be prima facie obvious to optimize the amount of improvement by the amount of treatment as a means to attain the desired therapeutic profile with a reasonable expectation of success. As there is a reduction in the CMT it would implicitly have a reduction of the CST (being the center of the macula); additionally as the same ophthalmic eyedrop is being given for the recited treatment it would be expected to have the same amount of reduction in CST after treatment as addressed by the instant specification.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 12397002 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Hutton (Oculis announces positive top line results from Phase 3 trial of OCS-01 drops for diabetic macular edema).
It is noted that Hutton falls under a 102(a)(1) date within a year of the instant priority date wherein the reference fall within the grace period and 102(b)(1) exceptions would apply.
The teachings of the patented claims in view of Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop formulation that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The patented claims in view of Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Hutton teaches that dexamethasone eyedrops (OCS-01) was given to diabetic macular edema patients six times daily for a six week loading phase and then 3 times daily for a six week maintenance phase; wherein there was a mean BCVA ETDRS score of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the dexamethasone eyedrop as suggested by Hutton and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success as it show a significant/unexpected improvement in the disease condition.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 12397002 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Oculis (Rethinking Ophthalmology –Oculis R&D Retina Day presentation 7/11/2023) or alternatively Oculis (Rethinking Ophthalmology – Investor Webcast 4/13/2023) or Oculis (Rethinking Ophthalmology –Jefferies Healthcare Conference 6/9/2023), or Tadayoni et al. (A 12-week Phase 2/3 Double-masked, Randomized, Multicenter Study of OCS-01 OPTIREACH Technology Topical Dexamethasone Eye Drops in Subjects with Diabetic Macular Edema (DME): Efficacy and Safety Findings).
It is noted that the secondary references to Oculis and Tadayoni et al. fall under 102(a)(1) dates within a year of the instant priority date wherein the references fall within the grace period and 102(b)(1) exceptions would apply.
Rejection:
The teachings of the patented claims in view of Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop embodiment that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The patented claims in view of Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Oculis (Rethinking Ophthalmology - Oculis R&D Retina Day) teaches that dexamethasone eyedrops 1.5%(15mg/ml, OCS-01) was given to diabetic macular edema patients six times daily for a six weeks and then 3 times daily for a six weeks (loading dose and then maintenance dose); wherein there was a mean BCVA ETDRS endpoint with statistically significant including scores of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%, Pages 7-8, 11-12, 15-20). Alternatively, the similar teachings are found in Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al. (Pages 3, 5, 11). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the taught dexamethasone eyedrop as suggested by Oculis (Rethinking Ophthalmology -Investor Webcast) or alternatively Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al.; and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success for show a significant/unexpected improvement in the disease condition.
Claims 1, 3, 6, 17-18, 20-23, 27-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12403148 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops).
The patented independent claims are directed to an aqueous composition in a container such as a plastic container comprising
i) 1-4% w/v of dexamethasone;
ii) 5-25% w/v of γ-cyclodextrin;
iii) 0.05-1% w/v of sodium thiosulfate; and,
iv) water; wherein the composition comprises a microsuspension comprising solid complexes of dexamethasone and γ-cyclodextrin (has no preservative), and a pH of 4.5-6. The dependent claims are to specific concentrations of dexamethasone and cyclodextrin and sodium thiosulfate, types and concentration of poloxamer, 0-1% electrolyte like sodium chloride, the size of the dexamethasone/cyclodextrin complex, and 0-0.2% and 0.1% disodium edetate.
While the patented claims do not recite the exact claimed values for the components, they do embrace the claimed ranges wherein it would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize within the taught range and arrive at the claimed values as a means of attaining the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values.
The patented claims does not expressly teach the instant claimed method of treating diabetic macular edema, the dosing regimen, poloxamer 407, disodium edetate, sodium chloride, the size of the solid dexamethasone/cyclodextrin complex, and usefulness for VEGF naïve patients; but does teach an ophthalmic composition comprising the dexamethasone, cyclodextrin, sodium thiosulfate, and water with a pH of 4.5-6.
Loftsson et al. teaches a dexamethasone/cyclodextrin/antioxidant aqueous formulation known for treating diabetic macular edema with the specific embodiment of
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0-0.2% of stabilizing agent, for example 0.1% of disodium edetate;
0-1% of electrolyte, for example 0.57% of sodium chloride;
0% to 0.6% of an additive to prevent the oxidation of the dexamethasone like sodium thiosulfate, for example between 0.1% and 0.5%, or between 0.2% and 0.4%;
that the preferred dosing of 1.5%w/v dexamethasone is 1-6 drops a day for a duration of at least 6, 7, 8, 9, 10, 11, or 12 weeks (Page 25 line 33-Page 26 line 23). That polymers like poloxamers are useful as stabilizers (Page 14 line 1-20, Page 15 line 1-20). That the solid complex of the drug and cyclodextrin has a D50 more particularly about 1um-about 10um as having it less than 10um prevents irritation of the eye (Page 9 line 1-13, Page 10 line 1-5), that the treatment is useful for patients with no or inadequate response to VEGF inhibitors including those with retinal thickening in the affected eye due to diabetic macular edema (VEGF inhibitor naïve, Page 27 line 13-20), and that the central macular thickness (CMT) can be significantly reduced after 12 weeks of treatment in a patient suffering from DME, from baseline to at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME (Page 27 line 4-11), and the patient is a human patient (Page 27 line 21, Page 29-30, Page 35-36).
NHS (National Health Service) teaches that dexamethasone eye drops are known to be usually given at one eyedrop 4-6 times a day and once your symptoms are better the doctor may have you reduce the dose before stopping completely (Dosage, How long to use eye drops).
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the dexamethasone composition to treat diabetic macular edema in an initial dosing regimen and then lower the dosing regimen of the formulation, a known pH of the formulation, a known size of the solid dexamethasone/cyclodextrin complex, excipients like sodium edetate and poloxamer 407 and sodium chloride, and useful for a VEGF naïve subject as suggested by Loftsson et al. and NHS and produce the claimed invention; as it is prima facie obvious to use and ophthalmic dexamethasone composition for its known treatment and dose the dexamethasone in its known regimen as taught by Loftsson et al. and NHS (i.e. 1 drop 6x/day) and to reduce the dose as the symptoms improve as established by NHS within the known parameters described by Loftsson et al. (i.e. 1 drop 1-3x/day) for as long as needed to achieve the desired therapeutic outcome (i.e. 6 weeks or more (e.g. 2 weeks until symptoms improve and 6 weeks or more at reduced dose until desired therapeutic outcome is achieved) in patients like VEGF naïve patients including those with retinal thickening in the affected eye due to diabetic macular edema, with a reasonable expectation of success absent evidence of criticality for the recited dose and duration. It is also prima facie obvious to incorporate excipients that are known to be in a dexamethasone ophthalmic composition as a means of attain the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values.
While the patented claims do not expressly recite the D50 of the drug/cyclodextrin complex, the prior art teaches that the solid complex of the drug/cyclodextrin can have a D50 of about 1um-about 10um wherein it is prima facie obvious to formulate the solid drug/cyclodextrin complex in this known range as having it less than 10um prevents irritation of the eye which is desirable with a reasonable expectation of success.
While the exact claimed mean ETDRS letters of improvement or central subfield thickness (CST) are not recited, the reduction of the central macular thickness (CMT) is embraced by the taught range (reduced after 12 weeks of treatment with the recited formulation in a patient suffering from DME by at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME) where it would be prima facie obvious to optimize the amount of improvement by the amount of treatment as a means to attain the desired therapeutic profile with a reasonable expectation of success. As there is a reduction in the CMT it would implicitly have a reduction of the CST (being the center of the macula); additionally as the same ophthalmic eyedrop is being given for the recited treatment it would be expected to have the same amount of reduction in CST after treatment as addressed by the instant specification.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12403148 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Hutton (Oculis announces positive top line results from Phase 3 trial of OCS-01 drops for diabetic macular edema).
It is noted that Hutton falls under a 102(a)(1) date within a year of the instant priority date wherein the reference fall within the grace period and 102(b)(1) exceptions would apply.
The teachings of the patented claims in view of Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop formulation that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The patented claims in view of Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Hutton teaches that dexamethasone eyedrops (OCS-01) was given to diabetic macular edema patients six times daily for a six week loading phase and then 3 times daily for a six week maintenance phase; wherein there was a mean BCVA ETDRS score of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the dexamethasone eyedrop as suggested by Hutton and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success as it show a significant/unexpected improvement in the disease condition.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12403148 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Oculis (Rethinking Ophthalmology –Oculis R&D Retina Day presentation 7/11/2023) or alternatively Oculis (Rethinking Ophthalmology – Investor Webcast 4/13/2023) or Oculis (Rethinking Ophthalmology –Jefferies Healthcare Conference 6/9/2023), or Tadayoni et al. (A 12-week Phase 2/3 Double-masked, Randomized, Multicenter Study of OCS-01 OPTIREACH Technology Topical Dexamethasone Eye Drops in Subjects with Diabetic Macular Edema (DME): Efficacy and Safety Findings).
It is noted that the secondary references to Oculis and Tadayoni et al. fall under 102(a)(1) dates within a year of the instant priority date wherein the references fall within the grace period and 102(b)(1) exceptions would apply.
Rejection:
The teachings of the patented claims in view of Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop embodiment that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The patented claims in view of Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Oculis (Rethinking Ophthalmology - Oculis R&D Retina Day) teaches that dexamethasone eyedrops 1.5%(15mg/ml, OCS-01) was given to diabetic macular edema patients six times daily for a six weeks and then 3 times daily for a six weeks (loading dose and then maintenance dose); wherein there was a mean BCVA ETDRS endpoint with statistically significant including scores of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%, Pages 7-8, 11-12, 15-20). Alternatively, the similar teachings are found in Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al. (Pages 3, 5, 11). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the taught dexamethasone eyedrop as suggested by Oculis (Rethinking Ophthalmology -Investor Webcast) or alternatively Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al.; and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success for show a significant/unexpected improvement in the disease condition.
Claims 1, 3, 6, 17-18, 20-23, 27-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9-16, 19-29 of U.S. Patent No. 12521448 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops).
The patented claims are directed to an aqueous composition comprising
i) about 1-about 2% w/v of dexamethasone;
ii) about 12-about 16% w/v of γ-cyclodextrin;
iii) about 2.2-about 2.8% of a polymer;
iv) 0-about 0.2% disodium edetate;
v) 0-about 1% electrolyte; and,
vi) water; wherein the composition comprises a microsuspension comprising solid complexes of dexamethasone and γ-cyclodextrin (has no preservative) with a diameter of about 1-about 10microns. The dependent claims are to specific concentrations of dexamethasone and cyclodextrin and sodium thiosulfate, types and concentration of poloxamer, the electrolyte to be sodium chloride at about 0.57%, the pH of about 5-about 6, and about 0.1% disodium edetate.
Independent claim 27 recites the dexamethasone at about 1.5% w/v, the cyclodextrin at about 14%w/v, the polymer to be poloxamer 407 at about 2.5%w/v, disodium edetate at about 0.1%. The dependent claim goes to a pH of about 5-about 6.
While the patented claims do not recite the exact claimed values for the components, they do embrace the claimed ranges wherein it would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize within the taught range and arrive at the claimed values as a means of attaining the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values.
The patented claims does not expressly teach the instant claimed method of treating diabetic macular edema, the dosing regimen, poloxamer 407, sodium chloride at the electrolyte, the liquid being in a plastic vial, and usefulness for VEGF naïve patients; but does teach an ophthalmic composition comprising the dexamethasone, cyclodextrin, polymer, disodium edetate, electrolyte, and water in certain ranges; and it is implicit that the liquid would have to be in a container.
Loftsson et al. teaches a dexamethasone/cyclodextrin/antioxidant aqueous formulation known for treating diabetic macular edema with the specific embodiment of
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0-0.2% of stabilizing agent, for example 0.1% of disodium edetate;
0-1% of electrolyte, for example 0.57% of sodium chloride;
0% to 0.6% of an additive to prevent the oxidation of the dexamethasone like sodium thiosulfate, for example between 0.1% and 0.5%, or between 0.2% and 0.4%;
that the preferred dosing of 1.5%w/v dexamethasone is 1-6 drops a day for a duration of at least 6, 7, 8, 9, 10, 11, or 12 weeks (Page 25 line 33-Page 26 line 23). That polymers like poloxamers are useful as stabilizers (Page 14 line 1-20, Page 15 line 1-20). That the solid complex of the drug and cyclodextrin has a D50 more particularly about 1um-about 10um as having it less than 10um prevents irritation of the eye (Page 9 line 1-13, Page 10 line 1-5), that the liquid composition can be stored in plastic vials (Page 20 line 1-3), that the treatment is useful for patients with no or inadequate response to VEGF inhibitors including those with retinal thickening in the affected eye due to diabetic macular edema (VEGF inhibitor naïve, Page 27 line 13-20), and that the central macular thickness (CMT) can be significantly reduced after 12 weeks of treatment in a patient suffering from DME, from baseline to at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME (Page 27 line 4-11), and the patient is a human patient (Page 27 line 21, Page 29-30, Page 35-36).
NHS (National Health Service) teaches that dexamethasone eye drops are known to be usually given at one eyedrop 4-6 times a day and once your symptoms are better the doctor may have you reduce the dose before stopping completely (Dosage, How long to use eye drops).
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the dexamethasone composition to treat diabetic macular edema in an initial dosing regimen and then lower the dosing regimen of the formulation, a known pH of the formulation, a known size of the solid dexamethasone/cyclodextrin complex, excipients like sodium edetate and poloxamer 407 and sodium chloride, be in a known container like a plastic vial, and useful for a VEGF naïve subject as suggested by Loftsson et al. and NHS and produce the claimed invention; as it is prima facie obvious to use and ophthalmic dexamethasone composition for its known treatment and dose the dexamethasone in its known regimen as taught by Loftsson et al. and NHS (i.e. 1 drop 6x/day) and to reduce the dose as the symptoms improve as established by NHS within the known parameters described by Loftsson et al. (i.e. 1 drop 1-3x/day) for as long as needed to achieve the desired therapeutic outcome (i.e. 6 weeks or more (e.g. 2 weeks until symptoms improve and 6 weeks or more at reduced dose until desired therapeutic outcome is achieved) in patients like VEGF naïve patients including those with retinal thickening in the affected eye due to diabetic macular edema, with a reasonable expectation of success absent evidence of criticality for the recited dose and duration. It is also prima facie obvious to incorporate excipients that are known to be in a dexamethasone ophthalmic composition as a means of attain the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values and be in a conventional container.
While the exact claimed mean ETDRS letters of improvement or central subfield thickness (CST) are not recited, the reduction of the central macular thickness (CMT) is embraced by the taught range (reduced after 12 weeks of treatment with the recited formulation in a patient suffering from DME by at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME) where it would be prima facie obvious to optimize the amount of improvement by the amount of treatment as a means to attain the desired therapeutic profile with a reasonable expectation of success. As there is a reduction in the CMT it would implicitly have a reduction of the CST (being the center of the macula); additionally as the same ophthalmic eyedrop is being given for the recited treatment it would be expected to have the same amount of reduction in CST after treatment as addressed by the instant specification.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9-16, 19-29 of U.S. Patent No. 12521448 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Hutton (Oculis announces positive top line results from Phase 3 trial of OCS-01 drops for diabetic macular edema).
It is noted that Hutton falls under a 102(a)(1) date within a year of the instant priority date wherein the reference fall within the grace period and 102(b)(1) exceptions would apply.
The teachings of the patented claims in view of Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop formulation that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The patented claims in view of Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Hutton teaches that dexamethasone eyedrops (OCS-01) was given to diabetic macular edema patients six times daily for a six week loading phase and then 3 times daily for a six week maintenance phase; wherein there was a mean BCVA ETDRS score of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the dexamethasone eyedrop as suggested by Hutton and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success as it show a significant/unexpected improvement in the disease condition.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9-16, 19-29 of U.S. Patent No. 12521448 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Oculis (Rethinking Ophthalmology –Oculis R&D Retina Day presentation 7/11/2023) or alternatively Oculis (Rethinking Ophthalmology – Investor Webcast 4/13/2023) or Oculis (Rethinking Ophthalmology –Jefferies Healthcare Conference 6/9/2023), or Tadayoni et al. (A 12-week Phase 2/3 Double-masked, Randomized, Multicenter Study of OCS-01 OPTIREACH Technology Topical Dexamethasone Eye Drops in Subjects with Diabetic Macular Edema (DME): Efficacy and Safety Findings).
It is noted that the secondary references to Oculis and Tadayoni et al. fall under 102(a)(1) dates within a year of the instant priority date wherein the references fall within the grace period and 102(b)(1) exceptions would apply.
Rejection:
The teachings of the patented claims in view of Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop embodiment that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The patented claims in view of Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Oculis (Rethinking Ophthalmology - Oculis R&D Retina Day) teaches that dexamethasone eyedrops 1.5%(15mg/ml, OCS-01) was given to diabetic macular edema patients six times daily for a six weeks and then 3 times daily for a six weeks (loading dose and then maintenance dose); wherein there was a mean BCVA ETDRS endpoint with statistically significant including scores of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%, Pages 7-8, 11-12, 15-20). Alternatively, the similar teachings are found in Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al. (Pages 3, 5, 11). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the taught dexamethasone eyedrop as suggested by Oculis (Rethinking Ophthalmology -Investor Webcast) or alternatively Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al.; and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success for show a significant/unexpected improvement in the disease condition.
Claims 1, 3, 6, 17-18, 20-21, 23, 27-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 and 26 of copending Application No. 18/792377 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops).
The copending claim 26 is directed to the method of treating diabetic macular edema with the administration with an aqueous ophthalmic composition comprising
i) 1-4% w/v of dexamethasone;
ii) 1-35% w/v of γ-cyclodextrin;
iii) 0.01-5% of sorbic acid or sorbate salt (preservative);
iv) 0-0.2% w/v of stabilizing agent;
v) 0-0.8% w/v of an antioxidant;
vi) 0-1% w/v of an electrolyte; and,
vii) water; a pH of 4.5-5.5 wherein the composition comprises a microsuspension comprising solid complexes of dexamethasone and γ-cyclodextrin.
Copending independent claim 1 is to the composition recited above, its dependent claims are to specific ranges or values for the dexamethasone, cyclodextrin, sorbic/sorbate salt, stabilizing agent like disodium edetate, antioxidant like sodium thiosulfate; the inclusion of a poloxamer in ranges like 2.2-2.8% and about 2.5%w/v, and that the electrolyte is sodium chloride.
While the copending claims do not recite the exact claimed values for the components, they do embrace the claimed ranges wherein it would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize within the taught range and arrive at the claimed values as a means of attaining the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values.
The copending claim 26 does not expressly teach the instant claimed dosing regimen, a poloxamer, the electrolyte to be sodium chloride, the stabilizing agent to be disodium edetate, the antioxidant to be sodium thiosulfate, the size of the solid dexamethasone/cyclodextrin complex, for the formulation to be in a plastic vial, and usefulness for VEGF naïve patients; but does teach the treatment of diabetic macular edema with the aqueous dexamethasone/γ-cyclodextrin complex formulation with a stabilizing agent, antioxidant, and electrolyte.
Loftsson et al. teaches treating diabetic macular edema with the dexamethasone/cyclodextrin aqueous formulation (Page 21, Page 25 line 33-Page 26 line 23), that the preferred dosing of 1.5%w/v dexamethasone is 1-6 drops a day for a duration of at least 6, 7, 8, 9, 10, 11, or 12 weeks. Loftsson et al. also teaches that polymers like poloxamers which are useful as stabilizers and from 2.2-2.8%w/v, the electrolyte can be sodium chloride, that the stabilizing agent can be disodium edetate, and an electrolyte like sodium chloride in various amounts including 0.2-1%w/v (Page 13 line 10-20, Page 15 line 1-20, Page 19 line 19-35). The aqueous composition can be stored in plastic vials (Page 20 line 1-3), and the treatment is useful for patients with no or inadequate response to VEGF inhibitors including those with retinal thickening in the affected eye due to diabetic macular edema (VEGF inhibitor naïve, Page 27 line 13-20). The solid complex of the drug and cyclodextrin has a D50 more particularly about 1um-about 10um as having it less than 10um prevents irritation of the eye (Page 9 line 1-13, Page 10 line 1-5), and that the central macular thickness (CMT) can be significantly reduced after 12 weeks of treatment in a patient suffering from DME, and have improved pin hole visual acuity from baseline to at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME (Page 27 line 4-11), and the patient is a human patient (Page 27 line 21, Page 29-30, Page 35-36).
NHS (National Health Service) teaches that dexamethasone eye drops are known to be usually given at one eyedrop 4-6 times a day and once your symptoms are better the doctor may have you reduce the dose before stopping completely (Dosage, How long to use eye drops).
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have an initial dosing regimen and then lower the dosing regimen of the formulation, incorporate a poloxamer, utilize sodium chloride and disodium edetate and sodium thiosulfate, have the size of the solid dexamethasone/cyclodextrin complex be 1-10um, and have the formulation in a plastic vial, and useful for VEGF naïve patients as suggested by Loftsson et al. and NHS and produce the claimed invention; as it is prima facie obvious to dose dexamethasone in its known regimen as taught by Loftsson et al. and NHS (i.e. 1 drop 6x/day) and to reduce the dose as the symptoms improve as established by NHS within the known parameters described by Loftsson et al. (i.e. 1 drop 1-3x/day) for as long as needed to achieve the desired therapeutic outcome (i.e. 6 weeks or more (e.g. 2 weeks until symptoms improve and 6 weeks or more at reduced dose until desired therapeutic outcome is achieved) in patients like VEGF naïve patients including those with retinal thickening in the affected eye due to diabetic macular edema, with a reasonable expectation of success absent evidence of criticality for the recited dose and duration. It is also prima facie obvious to incorporate known excipients useful in a dexamethasone/cyclodextrin formulation like poloxamers that are also stabilizers in their taught range, and utilize a known electrolyte like sodium chloride and known stabilizing agent and antioxidant (disodium edetate and sodium thiosulfate respectively) for the formulation with a reasonable expectation of success.
The copending claims 1-22 do not expressly recite the method of treatment of diabetic macular edema but does teach the aqueous dexamethasone/γ-cyclodextrin complex formulation with a stabilizing agent, antioxidant, and electrolyte.
Loftsson et al. teaches a dexamethasone/cyclodextrin/antioxidant aqueous formulation known for treating diabetic macular edema with the specific embodiment of
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0-0.2% of stabilizing agent, for example 0.1% of disodium edetate;
0-1% of electrolyte, for example 0.57% of sodium chloride;
0% to 0.6% of an additive to prevent the oxidation of the dexamethasone like sodium thiosulfate, for example between 0.1% and 0.5%, or between 0.2% and 0.4%; and a pH between 4.5-6; that the preferred dosing of 1.5%w/v dexamethasone is 1-6 drops a day for a duration of at least 6, 7, 8, 9, 10, 11, or 12 weeks (Page 25 line 33-Page 26 line 23). That polymers like poloxamers are useful as stabilizers (Page 14 line 1-20, Page 15 line 1-20). That the solid complex of the drug and cyclodextrin has a D50 more particularly about 1um-about 10um as having it less than 10um prevents irritation of the eye (Page 9 line 1-13, Page 10 line 1-5), that the treatment is useful for patients with no or inadequate response to VEGF inhibitors including those with retinal thickening in the affected eye due to diabetic macular edema (VEGF inhibitor naïve, Page 27 line 13-20), and that the central macular thickness (CMT) can be significantly reduced after 12 weeks of treatment in a patient suffering from DME, from baseline to at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME (Page 27 line 4-11), and the patient is a human patient (Page 27 line 21, Page 29-30, Page 35-36).
NHS (National Health Service) teaches that dexamethasone eye drops are known to be usually given at one eyedrop 4-6 times a day and once your symptoms are better the doctor may have you reduce the dose before stopping completely (Dosage, How long to use eye drops).
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the dexamethasone composition to treat diabetic macular edema in an initial dosing regimen and then lower the dosing regimen of the formulation, a known pH of the formulation, a known size of the solid dexamethasone/cyclodextrin complex, excipients like sodium edetate and poloxamer 407 and sodium chloride, and useful for a VEGF naïve subject as suggested by Loftsson et al. and NHS and produce the claimed invention; as it is prima facie obvious to use and ophthalmic dexamethasone composition for its known treatment and dose the dexamethasone in its known regimen as taught by Loftsson et al. and NHS (i.e. 1 drop 6x/day) and to reduce the dose as the symptoms improve as established by NHS within the known parameters described by Loftsson et al. (i.e. 1 drop 1-3x/day) for as long as needed to achieve the desired therapeutic outcome (i.e. 6 weeks or more (e.g. 2 weeks until symptoms improve and 6 weeks or more at reduced dose until desired therapeutic outcome is achieved) in patients like VEGF naïve patients including those with retinal thickening in the affected eye due to diabetic macular edema, with a reasonable expectation of success absent evidence of criticality for the recited dose and duration. It is also prima facie obvious to incorporate excipients that are known to be in a dexamethasone ophthalmic composition as a means of attain the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values.
While the copending claims do not expressly recite the D50 of the drug/cyclodextrin complex, the prior art teaches that the solid complex of the drug/cyclodextrin can have a D50 of about 1um-about 10um wherein it is prima facie obvious to formulate the solid drug/cyclodextrin complex in this known range as having it less than 10um prevents irritation of the eye which is desirable with a reasonable expectation of success.
While the exact claimed mean ETDRS letters of improvement or central subfield thickness (CST) are not recited, the reduction of the central macular thickness (CMT) is embraced by the taught range (reduced after 12 weeks of treatment with the recited formulation in a patient suffering from DME by at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME) where it would be prima facie obvious to optimize the amount of improvement by the amount of treatment as a means to attain the desired therapeutic profile with a reasonable expectation of success. As there is a reduction in the CMT it would implicitly have a reduction of the CST (being the center of the macula); additionally as the same ophthalmic eyedrop is being given for the recited treatment it would be expected to have the same amount of reduction in CST after treatment as addressed by the instant specification.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments:
Applicant's arguments are centered on the assertion that the instant claims require a specific induction/maintenance dosage regimen and the copending claims to not recited any dosage regimen, and that the copending claims requires sorbic acid or sorbate salt which is absent in the instant claims. This is fully considered but not persuasive as Applicant’s arguments are to the copending claims individually and 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). As for Applicant’s arguments to sorbic acid or sorbate salt this is not persuasive as the instant claims are open to the inclusion of additional components (“comprising”).
Accordingly, the rejection stands.
Claim 35 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 and 26 of copending Application No. 18/792377 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Hutton (Oculis announces positive top line results from Phase 3 trial of OCS-01 drops for diabetic macular edema).
It is noted that Hutton falls under a 102(a)(1) date within a year of the instant priority date wherein the reference fall within the grace period and 102(b)(1) exceptions would apply.
The teachings of the copending claims in view of Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop formulation that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The copending claims in view of Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Hutton teaches that dexamethasone eyedrops (OCS-01) was given to diabetic macular edema patients six times daily for a six week loading phase and then 3 times daily for a six week maintenance phase; wherein there was a mean BCVA ETDRS score of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the dexamethasone eyedrop as suggested by Hutton and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success as it show a significant/unexpected improvement in the disease condition.
Claim 35 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 and 26 of copending Application No. 18/792377 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Oculis (Rethinking Ophthalmology –Oculis R&D Retina Day presentation 7/11/2023) or alternatively Oculis (Rethinking Ophthalmology – Investor Webcast 4/13/2023) or Oculis (Rethinking Ophthalmology –Jefferies Healthcare Conference 6/9/2023), or Tadayoni et al. (A 12-week Phase 2/3 Double-masked, Randomized, Multicenter Study of OCS-01 OPTIREACH Technology Topical Dexamethasone Eye Drops in Subjects with Diabetic Macular Edema (DME): Efficacy and Safety Findings).
It is noted that the secondary references to Oculis and Tadayoni et al. fall under 102(a)(1) dates within a year of the instant priority date wherein the references fall within the grace period and 102(b)(1) exceptions would apply.
Rejection:
The teachings of the copending claims in view of Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop embodiment that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The copending claims in view of Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Oculis (Rethinking Ophthalmology - Oculis R&D Retina Day) teaches that dexamethasone eyedrops 1.5%(15mg/ml, OCS-01) was given to diabetic macular edema patients six times daily for a six weeks and then 3 times daily for a six weeks (loading dose and then maintenance dose); wherein there was a mean BCVA ETDRS endpoint with statistically significant including scores of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%, Pages 7-8, 11-12, 15-20). Alternatively, the similar teachings are found in Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al. (Pages 3, 5, 11). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the taught dexamethasone eyedrop as suggested by Oculis (Rethinking Ophthalmology -Investor Webcast) or alternatively Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al.; and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success for show a significant/unexpected improvement in the disease condition.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3, 6, 17-18, 20-23, 27-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 25 of copending Application No. 18/792377 in view of Genentech (Diabetic Macular Edema (DME) Fact Sheet) and Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops).
The copending claim is directed to the method of treating diabetic retinopathy with the administration with an aqueous ophthalmic composition comprising
i) 1-4% w/v of dexamethasone;
ii) 1-35% w/v of γ-cyclodextrin;
iii) 0.01-5% of sorbic acid or sorbate salt (preservative);
iv) 0-0.2% w/v of stabilizing agent;
v) 0-0.8% w/v of an antioxidant;
vi) 0-1% w/v of an electrolyte; and,
vii) water; a pH of 4.5-5.5 wherein the composition comprises a microsuspension comprising solid complexes of dexamethasone and γ-cyclodextrin (has no preservative).
While the copending claim do not recite the exact claimed values for the components, they do embrace the claimed ranges wherein it would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize within the taught range and arrive at the claimed values as a means of attaining the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values.
The copending claim does not expressly teach the instant claimed dosing regimen for diabetic macular edema, a poloxamer, the electrolyte to be sodium chloride, the stabilizing agent to be disodium edetate, the antioxidant to be sodium thiosulfate, the size of the solid dexamethasone/cyclodextrin complex, for the formulation to be in a plastic vial, and usefulness for VEGF naïve patients; but does teach the treatment of diabetic retinopathy with the aqueous dexamethasone/γ-cyclodextrin complex formulation with a stabilizing agent, antioxidant, and electrolyte.
Genentech teaches that diabetic retinopathy that worsens can lead to diabetic macular edema, and that diabetic macular edema can occur at any stage of diabetic retinopathy although more likely as the disease progresses (paragraph 1-3).
Loftsson et al. teaches treating diabetic macular edema with the dexamethasone/cyclodextrin aqueous formulation (Page 21, Page 25 line 33-Page 26 line 23), that the preferred dosing of 1.5%w/v dexamethasone is 1-6 drops a day for a duration of at least 6, 7, 8, 9, 10, 11, or 12 weeks. Loftsson et al. also teaches that polymers like poloxamers which are useful as stabilizers and from 2.2-2.8%w/v, the electrolyte can be sodium chloride, that the stabilizing agent can be disodium edetate, and an electrolyte like sodium chloride in various amounts including 0.2-1%w/v (Page 13 line 10-20, Page 15 line 1-20, Page 19 line 19-35). The aqueous composition can be stored in plastic vials (Page 20 line 1-3), and the treatment is useful for patients with no or inadequate response to VEGF inhibitors including those with retinal thickening in the affected eye due to diabetic macular edema (VEGF inhibitor naïve, Page 27 line 13-20). The solid complex of the drug and cyclodextrin has a D50 more particularly about 1um-about 10um as having it less than 10um prevents irritation of the eye (Page 9 line 1-13, Page 10 line 1-5), and that the central macular thickness (CMT) can be significantly reduced after 12 weeks of treatment in a patient suffering from DME, and have improved pin hole visual acuity from baseline to at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME (Page 27 line 4-11), and the patient is a human patient (Page 27 line 21, Page 29-30, Page 35-36).
NHS (National Health Service) teaches that dexamethasone eye drops are known to be usually given at one eyedrop 4-6 times a day and once your symptoms are better the doctor may have you reduce the dose before stopping completely (Dosage, How long to use eye drops).
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat diabetic macular edema with an initial dosing regimen and then lower the dosing regimen of the formulation, incorporate a poloxamer, utilize sodium chloride and disodium edetate and sodium thiosulfate, have the size of the solid dexamethasone/cyclodextrin complex be 1-10um, and have the formulation in a plastic vial, and useful for VEGF naïve patients as suggested by Genentech and Loftsson et al. and NHS and produce the claimed invention; as it is prima facie obvious to not only treat diabetic retinopathy but its known complication of diabetic macular edema as addressed by Genentech with the taught dexamethasone in its known regimen as taught by Loftsson et al. and NHS (i.e. 1 drop 6x/day) and to reduce the dose as the symptoms improve as established by NHS within the known parameters described by Loftsson et al. (i.e. 1 drop 1-3x/day) for as long as needed to achieve the desired therapeutic outcome (i.e. 6 weeks or more (e.g. 2 weeks until symptoms improve and 6 weeks or more at reduced dose until desired therapeutic outcome is achieved) in patients like VEGF naïve patients including those with retinal thickening in the affected eye due to diabetic macular edema, with a reasonable expectation of success absent evidence of criticality for the recited dose and duration. It is also prima facie obvious to incorporate known excipients useful in a dexamethasone/cyclodextrin formulation like poloxamers that are also stabilizers in their taught range, and utilize a known electrolyte like sodium chloride and known stabilizing agent and antioxidant (disodium edetate and sodium thiosulfate respectively) for the formulation with a reasonable expectation of success.
While the copending claims do not expressly recite the D50 of the drug/cyclodextrin complex, the prior art teaches that the solid complex of the drug/cyclodextrin can have a D50 of about 1um-about 10um wherein it is prima facie obvious to formulate the solid drug/cyclodextrin complex in this known range as having it less than 10um prevents irritation of the eye which is desirable with a reasonable expectation of success.
While the exact claimed mean ETDRS letters of improvement or central subfield thickness (CST) are not recited, the reduction of the central macular thickness (CMT) is embraced by the taught range (reduced after 12 weeks of treatment with the recited formulation in a patient suffering from DME by at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME) where it would be prima facie obvious to optimize the amount of improvement by the amount of treatment as a means to attain the desired therapeutic profile with a reasonable expectation of success. As there is a reduction in the CMT it would implicitly have a reduction of the CST (being the center of the macula); additionally as the same ophthalmic eyedrop is being given for the recited treatment it would be expected to have the same amount of reduction in CST after treatment as addressed by the instant specification.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments:
Applicant's arguments are centered on the assertion that the instant claims require a specific induction/maintenance dosage regimen and the copending claims to not recited any dosage regimen, and that the copending claims requires sorbic acid or sorbate salt which is absent in the instant claims. This is fully considered but not persuasive as Applicant’s arguments are to the copending claims individually and 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). As for Applicant’s arguments to sorbic acid or sorbate salt this is not persuasive as the instant claims are open to the inclusion of additional components (“comprising”).
Accordingly, the rejection stands.
Claim 35 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 25 of copending Application No. 18/792377 in view of Genentech (Diabetic Macular Edema (DME) Fact Sheet) and Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Hutton (Oculis announces positive top line results from Phase 3 trial of OCS-01 drops for diabetic macular edema).
It is noted that Hutton falls under a 102(a)(1) date within a year of the instant priority date wherein the reference fall within the grace period and 102(b)(1) exceptions would apply.
The teachings of the copending claims in view of Genentech and Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop formulation that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The copending claims in view of Genentech and Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Hutton teaches that dexamethasone eyedrops (OCS-01) was given to diabetic macular edema patients six times daily for a six week loading phase and then 3 times daily for a six week maintenance phase; wherein there was a mean BCVA ETDRS score of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the dexamethasone eyedrop as suggested by Hutton and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success as it show a significant/unexpected improvement in the disease condition.
This is a provisional nonstatutory double patenting rejection.
Claim 35 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 25 of copending Application No. 18/792377 in view of Genentech (Diabetic Macular Edema (DME) Fact Sheet) and Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Oculis (Rethinking Ophthalmology –Oculis R&D Retina Day presentation 7/11/2023) or alternatively Oculis (Rethinking Ophthalmology – Investor Webcast 4/13/2023) or Oculis (Rethinking Ophthalmology –Jefferies Healthcare Conference 6/9/2023), or Tadayoni et al. (A 12-week Phase 2/3 Double-masked, Randomized, Multicenter Study of OCS-01 OPTIREACH Technology Topical Dexamethasone Eye Drops in Subjects with Diabetic Macular Edema (DME): Efficacy and Safety Findings).
It is noted that the secondary references to Oculis and Tadayoni et al. fall under 102(a)(1) dates within a year of the instant priority date wherein the references fall within the grace period and 102(b)(1) exceptions would apply.
Rejection:
The teachings of the copending claims in view of Genentech and Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop embodiment that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The copending claims in view of Genentech and Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Oculis (Rethinking Ophthalmology - Oculis R&D Retina Day) teaches that dexamethasone eyedrops 1.5%(15mg/ml, OCS-01) was given to diabetic macular edema patients six times daily for a six weeks and then 3 times daily for a six weeks (loading dose and then maintenance dose); wherein there was a mean BCVA ETDRS endpoint with statistically significant including scores of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%, Pages 7-8, 11-12, 15-20). Alternatively, the similar teachings are found in Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al. (Pages 3, 5, 11). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the taught dexamethasone eyedrop as suggested by Oculis (Rethinking Ophthalmology -Investor Webcast) or alternatively Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al.; and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success for show a significant/unexpected improvement in the disease condition.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3, 6, 17-18, 20-23, 27-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of copending Application No. 19313674 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops).
The copending independent claims are directed to an aqueous composition in a container such as a plastic container comprising
i) 1-4% w/v of dexamethasone;
ii) 5-25% w/v of γ-cyclodextrin;
iii) 0.05-1% w/v of sodium thiosulfate; and,
iv) water (has no preservative).
The dependent claims are to specific concentrations of dexamethasone and cyclodextrin and sodium thiosulfate, types and concentration of poloxamer, 0.1% electrolyte like sodium chloride, the size of the dexamethasone/cyclodextrin complex. Dependent claims are directed to particular concentrations of dexamethasone and cyclodextrin and sodium thiosulfate, types of poloxamer like 407 and its concentration, 0-0.2% and 0.1% disodium edetate, 0-1% electrolyte like sodium chloride, pH, and microparticle size.
While the copending claims do not recite the exact claimed values for the components, they do embrace the claimed ranges wherein it would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize within the taught range and arrive at the claimed values as a means of attaining the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values.
The copending claims does not expressly teach the instant claimed method of treating diabetic macular edema, the dosing regimen, poloxamer 407, disodium edetate, sodium chloride, a pH of 4.5-6, the size of the solid dexamethasone/cyclodextrin complex, and usefulness for VEGF naïve patients; but does teach an ophthalmic composition comprising the dexamethasone, cyclodextrin, sodium thiosulfate, and water.
Loftsson et al. teaches a dexamethasone/cyclodextrin/antioxidant aqueous formulation known for treating diabetic macular edema with the specific embodiment of
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0-0.2% of stabilizing agent, for example 0.1% of disodium edetate;
0-1% of electrolyte, for example 0.57% of sodium chloride;
0% to 0.6% of an additive to prevent the oxidation of the dexamethasone like sodium thiosulfate, for example between 0.1% and 0.5%, or between 0.2% and 0.4%; and a pH between 4.5-6;
that the preferred dosing of 1.5%w/v dexamethasone is 1-6 drops a day for a duration of at least 6, 7, 8, 9, 10, 11, or 12 weeks (Page 25 line 33-Page 26 line 23). That polymers like poloxamers are useful as stabilizers (Page 14 line 1-20, Page 15 line 1-20). That the solid complex of the drug and cyclodextrin has a D50 more particularly about 1um-about 10um as having it less than 10um prevents irritation of the eye (Page 9 line 1-13, Page 10 line 1-5), that the treatment is useful for patients with no or inadequate response to VEGF inhibitors including those with retinal thickening in the affected eye due to diabetic macular edema (VEGF inhibitor naïve, Page 27 line 13-20), and that the central macular thickness (CMT) can be significantly reduced after 12 weeks of treatment in a patient suffering from DME, from baseline to at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME (Page 27 line 4-11), and the patient is a human patient (Page 27 line 21, Page 29-30, Page 35-36).
NHS (National Health Service) teaches that dexamethasone eye drops are known to be usually given at one eyedrop 4-6 times a day and once your symptoms are better the doctor may have you reduce the dose before stopping completely (Dosage, How long to use eye drops).
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the dexamethasone composition to treat diabetic macular edema in an initial dosing regimen and then lower the dosing regimen of the formulation, a known pH of the formulation, a known size of the solid dexamethasone/cyclodextrin complex, excipients like sodium edetate and poloxamer 407 and sodium chloride, and useful for a VEGF naïve subject as suggested by Loftsson et al. and NHS and produce the claimed invention; as it is prima facie obvious to use and ophthalmic dexamethasone composition for its known treatment and dose the dexamethasone in its known regimen as taught by Loftsson et al. and NHS (i.e. 1 drop 6x/day) and to reduce the dose as the symptoms improve as established by NHS within the known parameters described by Loftsson et al. (i.e. 1 drop 1-3x/day) for as long as needed to achieve the desired therapeutic outcome (i.e. 6 weeks or more (e.g. 2 weeks until symptoms improve and 6 weeks or more at reduced dose until desired therapeutic outcome is achieved) in patients like VEGF naïve patients including those with retinal thickening in the affected eye due to diabetic macular edema, with a reasonable expectation of success absent evidence of criticality for the recited dose and duration. It is also prima facie obvious to incorporate excipients that are known to be in a dexamethasone ophthalmic composition as a means of attain the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values.
While the copending claims do not expressly recite the D50 of the drug/cyclodextrin complex, the prior art teaches that the solid complex of the drug/cyclodextrin can have a D50 of about 1um-about 10um wherein it is prima facie obvious to formulate the solid drug/cyclodextrin complex in this known range as having it less than 10um prevents irritation of the eye which is desirable with a reasonable expectation of success.
While the exact claimed mean ETDRS letters of improvement or central subfield thickness (CST) are not recited, the reduction of the central macular thickness (CMT) is embraced by the taught range (reduced after 12 weeks of treatment with the recited formulation in a patient suffering from DME by at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME) where it would be prima facie obvious to optimize the amount of improvement by the amount of treatment as a means to attain the desired therapeutic profile with a reasonable expectation of success. As there is a reduction in the CMT it would implicitly have a reduction of the CST (being the center of the macula); additionally as the same ophthalmic eyedrop is being given for the recited treatment it would be expected to have the same amount of reduction in CST after treatment as addressed by the instant specification.
This is a provisional nonstatutory double patenting rejection.
Claim 35 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of copending Application No. 19313674 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Hutton (Oculis announces positive top line results from Phase 3 trial of OCS-01 drops for diabetic macular edema).
It is noted that Hutton falls under a 102(a)(1) date within a year of the instant priority date wherein the reference fall within the grace period and 102(b)(1) exceptions would apply.
The teachings of the copending claims in view of Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop formulation that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The copending claims in view of Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Hutton teaches that dexamethasone eyedrops (OCS-01) was given to diabetic macular edema patients six times daily for a six week loading phase and then 3 times daily for a six week maintenance phase; wherein there was a mean BCVA ETDRS score of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the dexamethasone eyedrop as suggested by Hutton and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success as it show a significant/unexpected improvement in the disease condition.
This is a provisional nonstatutory double patenting rejection.
Claim 35 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of copending Application No. 19313674 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Oculis (Rethinking Ophthalmology –Oculis R&D Retina Day presentation 7/11/2023) or alternatively Oculis (Rethinking Ophthalmology – Investor Webcast 4/13/2023) or Oculis (Rethinking Ophthalmology –Jefferies Healthcare Conference 6/9/2023), or Tadayoni et al. (A 12-week Phase 2/3 Double-masked, Randomized, Multicenter Study of OCS-01 OPTIREACH Technology Topical Dexamethasone Eye Drops in Subjects with Diabetic Macular Edema (DME): Efficacy and Safety Findings).
It is noted that the secondary references to Oculis and Tadayoni et al. fall under 102(a)(1) dates within a year of the instant priority date wherein the references fall within the grace period and 102(b)(1) exceptions would apply.
Rejection:
The teachings of the copending claims in view of Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop embodiment that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The copending claims in view of Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Oculis (Rethinking Ophthalmology - Oculis R&D Retina Day) teaches that dexamethasone eyedrops 1.5%(15mg/ml, OCS-01) was given to diabetic macular edema patients six times daily for a six weeks and then 3 times daily for a six weeks (loading dose and then maintenance dose); wherein there was a mean BCVA ETDRS endpoint with statistically significant including scores of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%, Pages 7-8, 11-12, 15-20). Alternatively, the similar teachings are found in Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al. (Pages 3, 5, 11). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the taught dexamethasone eyedrop as suggested by Oculis (Rethinking Ophthalmology -Investor Webcast) or alternatively Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al.; and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success for show a significant/unexpected improvement in the disease condition.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3, 6, 17-18, 20-23, 27-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9-16, 19-29 of copending Application No. 19446758 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops).
The copending claims are directed to an ophthalmic microsuspension comprising
i) about 1-about 2% w/v of dexamethasone;
ii) about 12-about 16% w/v of γ-cyclodextrin;
iii) about 2.2-about 2.8% of a viscosity enhancing polymer;
iv) 0-about 0.2% disodium edetate;
v) 0-about 1% electrolyte; and,
vi) water; wherein the composition comprises a microsuspension comprising solid complexes of dexamethasone and γ-cyclodextrin (has no preservative) with a diameter of about 1-about 10microns. The dependent claims are to specific concentrations of dexamethasone and cyclodextrin, the types and concentration of poloxamer as the polymer, and the electrolyte to be sodium chloride at about 0.57%.
While the copending claims do not recite the exact claimed values for the components, they do embrace the claimed ranges wherein it would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize within the taught range and arrive at the claimed values as a means of attaining the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values.
The copending claims does not expressly teach the instant claimed method of treating diabetic macular edema, the dosing regimen, poloxamer 407, sodium chloride at the electrolyte, pH, the liquid being in a plastic vial, and usefulness for VEGF naïve patients; but does teach an ophthalmic composition comprising the dexamethasone, cyclodextrin, polymer, disodium edetate, electrolyte, and water in certain ranges; and it is implicit that the liquid would have to be in a container.
Loftsson et al. teaches a dexamethasone/cyclodextrin/antioxidant aqueous formulation known for treating diabetic macular edema with the specific embodiment of
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0-0.2% of stabilizing agent, for example 0.1% of disodium edetate;
0-1% of electrolyte, for example 0.57% of sodium chloride;
0% to 0.6% of an additive to prevent the oxidation of the dexamethasone like sodium thiosulfate, for example between 0.1% and 0.5%, or between 0.2% and 0.4%; the pH to be preferably from 4.5-6;
that the preferred dosing of 1.5%w/v dexamethasone is 1-6 drops a day for a duration of at least 6, 7, 8, 9, 10, 11, or 12 weeks (Page 25 line 33-Page 26 line 23). That polymers like poloxamers are useful as stabilizers (Page 14 line 1-20, Page 15 line 1-20). That the solid complex of the drug and cyclodextrin has a D50 more particularly about 1um-about 10um as having it less than 10um prevents irritation of the eye (Page 9 line 1-13, Page 10 line 1-5), that the liquid composition can be stored in plastic vials (Page 20 line 1-3), that the treatment is useful for patients with no or inadequate response to VEGF inhibitors including those with retinal thickening in the affected eye due to diabetic macular edema (VEGF inhibitor naïve, Page 27 line 13-20), and that the central macular thickness (CMT) can be significantly reduced after 12 weeks of treatment in a patient suffering from DME, from baseline to at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME (Page 27 line 4-11), and the patient is a human patient (Page 27 line 21, Page 29-30, Page 35-36).
NHS (National Health Service) teaches that dexamethasone eye drops are known to be usually given at one eyedrop 4-6 times a day and once your symptoms are better the doctor may have you reduce the dose before stopping completely (Dosage, How long to use eye drops).
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the dexamethasone composition to treat diabetic macular edema in an initial dosing regimen and then lower the dosing regimen of the formulation, a known pH of the formulation, a known size of the solid dexamethasone/cyclodextrin complex, excipients like sodium edetate and poloxamer 407 and sodium chloride, be in a known container like a plastic vial, and useful for a VEGF naïve subject as suggested by Loftsson et al. and NHS and produce the claimed invention; as it is prima facie obvious to use and ophthalmic dexamethasone composition for its known treatment and dose the dexamethasone in its known regimen as taught by Loftsson et al. and NHS (i.e. 1 drop 6x/day) and to reduce the dose as the symptoms improve as established by NHS within the known parameters described by Loftsson et al. (i.e. 1 drop 1-3x/day) for as long as needed to achieve the desired therapeutic outcome (i.e. 6 weeks or more (e.g. 2 weeks until symptoms improve and 6 weeks or more at reduced dose until desired therapeutic outcome is achieved) in patients like VEGF naïve patients including those with retinal thickening in the affected eye due to diabetic macular edema, with a reasonable expectation of success absent evidence of criticality for the recited dose and duration. It is also prima facie obvious to incorporate excipients that are known to be in a dexamethasone ophthalmic composition as a means of attain the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed values and be in a conventional container.
While the exact claimed mean ETDRS letters of improvement or central subfield thickness (CST) are not recited, the reduction of the central macular thickness (CMT) is embraced by the taught range (reduced after 12 weeks of treatment with the recited formulation in a patient suffering from DME by at least 3 ETDRS letters after 12 weeks of treatment in patients suffering from DME) where it would be prima facie obvious to optimize the amount of improvement by the amount of treatment as a means to attain the desired therapeutic profile with a reasonable expectation of success. As there is a reduction in the CMT it would implicitly have a reduction of the CST (being the center of the macula); additionally as the same ophthalmic eyedrop is being given for the recited treatment it would be expected to have the same amount of reduction in CST after treatment as addressed by the instant specification.
This is a provisional nonstatutory double patenting rejection.
Claim 35 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9-16, 19-29 of copending Application No. 19446758 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Hutton (Oculis announces positive top line results from Phase 3 trial of OCS-01 drops for diabetic macular edema).
It is noted that Hutton falls under a 102(a)(1) date within a year of the instant priority date wherein the reference fall within the grace period and 102(b)(1) exceptions would apply.
The teachings of the copending claims in view of Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop formulation that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The copending claims in view of Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Hutton teaches that dexamethasone eyedrops (OCS-01) was given to diabetic macular edema patients six times daily for a six week loading phase and then 3 times daily for a six week maintenance phase; wherein there was a mean BCVA ETDRS score of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the dexamethasone eyedrop as suggested by Hutton and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success as it show a significant/unexpected improvement in the disease condition.
This is a provisional nonstatutory double patenting rejection.
Claim 35 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9-16, 19-29 of copending Application No. 19446758 in view of Loftsson et al. (WO 2021/001366) and National Health Service (NHS) (How and when to use dexamethasone eye drops) as applied to claims 1, 3, 6, 17-18, 20-23, 27-32 above, further in view of Oculis (Rethinking Ophthalmology –Oculis R&D Retina Day presentation 7/11/2023) or alternatively Oculis (Rethinking Ophthalmology – Investor Webcast 4/13/2023) or Oculis (Rethinking Ophthalmology –Jefferies Healthcare Conference 6/9/2023), or Tadayoni et al. (A 12-week Phase 2/3 Double-masked, Randomized, Multicenter Study of OCS-01 OPTIREACH Technology Topical Dexamethasone Eye Drops in Subjects with Diabetic Macular Edema (DME): Efficacy and Safety Findings).
It is noted that the secondary references to Oculis and Tadayoni et al. fall under 102(a)(1) dates within a year of the instant priority date wherein the references fall within the grace period and 102(b)(1) exceptions would apply.
Rejection:
The teachings of the copending claims in view of Loftsson et al. and NHS are addressed above, including the method of treating diabetic macular edema with a dexamethasone eyedrop. The method include a dexamethasone eyedrop embodiment that contains:
1.5% of dexamethasone;
14% of γ-cyclodextrin;
2.5% of poloxamer like poloxamer 407;
0.1% of disodium edetate;
0.57% of sodium chloride;
0.2-0.4% sodium thiosulfate;
and water; wherein the % are w/v.
The copending claims in view of Loftsson et al. and NHS does not recite the exact dosing regimen for treating diabetic macular edema with the recited eyedrop and level of improvement which was unexpected.
However Oculis (Rethinking Ophthalmology - Oculis R&D Retina Day) teaches that dexamethasone eyedrops 1.5%(15mg/ml, OCS-01) was given to diabetic macular edema patients six times daily for a six weeks and then 3 times daily for a six weeks (loading dose and then maintenance dose); wherein there was a mean BCVA ETDRS endpoint with statistically significant including scores of 7.2 letters at week 6 and sustained to week 12 with statistical significance (7.6 letters), and a higher percentage of patients that achieved ≥15 letter improvement from baseline at week 6 (25.3%) and sustained to week 12 (27.4%, Pages 7-8, 11-12, 15-20). Alternatively, the similar teachings are found in Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al. (Pages 3, 5, 11). It is noted that OCS-01 is the formulation of Loftsson as addressed by the instant specification.
Wherein it would be obvious to one of ordinary skill in the art to utilize the dosing regimen for the taught dexamethasone eyedrop as suggested by Oculis (Rethinking Ophthalmology -Investor Webcast) or alternatively Oculis (Rethinking Ophthalmology -Investor Webcast, Page 14-17), Oculis (Rethinking Ophthalmology – Jefferies Healthcare Conference 6/9/2023, Pages 10-16), or Tadayoni et al.; and produce the claimed invention as it is prima facie obvious to utilize a dosing regimen for the same drug treating the same disease condition with a reasonable expectation of success for show a significant/unexpected improvement in the disease condition.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1, 3, 6, 17-18, 20-23, 27-32, 35 are rejected.
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/GIGI G HUANG/Primary Examiner, Art Unit 1613
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