DETAILED ACTION
Status of Application
The response filed 07/28/2025 has been received, entered and carefully considered. The response affects the instant application accordingly:
Claims 1-2, 5-6, 17-18, 20-22, 26-28 have been amended.
Claims 7-16, 19 has been cancelled.
Claims 29-35 has been added.
Claims 1-6, 17-18, 20-35 are pending.
Claims 1-6, 17-18, 20-35 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All grounds not addressed in the action are withdrawn or moot as a result of amendment.
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 1-6, 17-18, 20-35 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.
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 that Oculis Phase II Clinical trials with 1.5% dexamethasone γ-cyclodextrin suspension are those described in Loftsson Page 35-36 which was one drop 3x/day for 12 weeks had a Mean CMT change from baseline at week 12 of -56.83um with a difference of -36.77um with a p=0.0123 and a mean BCVA change from baseline at week 12 of 2.62 ETDRS letters with a difference of 1.58 letters and p=0.1258, that the formulation of the 1.5% dexamethasone γ-cyclodextrin in Loftsson is also that of the instant claims but the dosage regimen was changed from the one exemplified in Loftsson in Phase II/III Clinic Trial to be the Loftsson 1.5% dexamethasone γ-cyclodextrin suspension 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) with a 7.2 letter gain in BCVA at week 6 (p=0.007) and 7.6 letter gain in BCVA at week 12 (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), and rapid sustained reduction in retinal edema already at Week 2; asserting that one would not have predicted these results in advance and that Loftsson discloses a genus of 42 separate dosage regimes and only exemplified one and the prior art of Loftsson does not teach the specific claimed loading dose with the maintenance dose claimed wherein it is unobvious over the prior art, as the NHS reference refers to the use of dexamethasone for anterior disorders not posterior ocular disorders as there are no commercial topical eye drop to treat posterior DME using dexamethasone.
This is fully considered but not persuasive.
First any evidence submitted to traverse the rejection must be by way of an oath or declaration/affidavit. Applicant’s evidence and data and statements of lack of topical treatment for DME (unmet need) is not in proper form as it is not submitted as an affidavit/declaration under 1.132.
Second, Applicant was not clear and explicit as to the components of the Loftsson 1.5% dexamethasone γ-cyclodextrin suspension formulation utilized in the Phase II/III clinical trial, but Applicant appears to be directed to Table 3 or possibly one on Page 26. The showing does appear to demonstrate that the specific regimen of the Loftsson 1.5% dexamethasone γ-cyclodextrin suspension 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 there was even further gain 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, but there continued to have improvement at the maintenance dose; while the Phase II trial showed some improve in the ETDRS letters at 3 drops/day after 12 weeks but appears to not be statistically significant (if p=0.1258 is p value is 0.125 which is >0.05).
Third, if this data is as treated above – the claims are not commensurate in scope with the showing (which would have to be in an affidavit/declaration under 1.132 to be evidence to the prior art rejection) as the claims are broader than the formulation used for the treatment and the claims must be commensurate in scope with a showing of non-obviousness.
Accordingly, the rejection stands.
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 1-6, 17-18, 20-35 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 which are addressed above.
Accordingly, the rejection stands.
Claims 1-6, 17-18, 20-35 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 (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 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 which are addressed above.
Accordingly, the rejection stands.
Claims 1-6, 17-18, 20-35 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 which are addressed above.
Accordingly, the rejection stands.
Claims 1-6, 17-18, 20-35 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;
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 which are addressed above.
Accordingly, the rejection stands.
Claims 1-6, 17-18, 20-35 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;
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 which are addressed above.
Accordingly, the rejection stands.
Claims 1-6, 17-18, 20-21, 23-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 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 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 (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, 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