DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statement (IDS) was submitted and filed on 07/18/2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. See the signed and attached 1449 form.
Status of Application
Applicants' arguments/remarks filed 07/15/2025 are acknowledged. No claim is currently amended. Claims 1-3, 5-11, 13-19, and 21-25 are examined on the merits within and are currently pending.
Maintained Rejections
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or non-obviousness.
Claims 1-3, 5-7, 9-11, 13-15, 17-19 and 21-23 are rejected under 35 U.S.C. 103 as being obvious over Bhutada et al. (US 20120283252 A1) in view of Koenen et al. (WO 03099278 Al).
With regard to claim 1, Bhutada et al. teach “Pharmaceutical Ophthalmic Compositions (0017) comprising:
roflumilast (0020), the active ingredient content may vary depending on type of active, diseases to be treated and the like, it is generally present in a proportion of 0.005- 20.0 w/v %, preferably 0.005-5.0 w/v % relative to the entire composition. (0022);
viscosity agents including hydroxypropyl methylcellulose, which is water-soluble polymer, is generally present in a composition in a proportion of 0.01-2.0 w/v %, relative to the entire composition. (0023);
surfactants, the nonionic surfactant is generally contained in a proportion of 0.005-1.0 w/v %, and more preferably 0.05-0.3 w/v % relative to the entire composition. (0024);
and buffers, generally contained in a proportion of 0.01-2.0 w/v %, relative to the entire composition. (0027).
The buffer should have buffering capacity in the range of pH 5.0-8.5. (0027).
Roflumilast (0020) is one of the optional active agents.
In addition, Koenen et al. teach Roflumilast as the active agent for the ophthalmological use to treat of the diseases of the eyes.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare an ophthalmic pharmaceutical composition comprising:
a therapeutically effective amount of roflumilast; a viscosity agent comprising hydroxypropyl methylcellulose; a surfactant; and a buffer, taught by Bhutada et al., and to have roflumilast as the active agent and pH range taught by Bhutada et al. and Koenen et al. since they have proven it is suitable to do so.
With regard to claim 2, Bhutada et al. teach polysorbate is as the surfactant in examples 5-7, (0052-0054).
With regard to claim 3, Bhutada et al. teach phosphate and citrate buffers (0027) and (0028).
With regard to claim 5, Bhutada et al. teach the suspension (0018).
With regard to claims 6 and 7 Bhutada et al. teach a particle size distribution range: 0.01-100, 0.01-50, 0.01-30, 0.1-20, or 0.01-5.0 μm, (Brief manufacturing procedure, Step-C: Preparation of final composition (In aseptic area)).
With regard to claim 9, Bhutada et al. teach “Pharmaceutical Ophthalmic Compositions (0017) comprising:
roflumilast (0020), the active ingredient content may vary depending on type of active, diseases to be treated and the like, preferably 0.005-5.0 w/v %. (0022);
viscosity agents including polyvinylpyrrolidone, is generally present in a composition in a proportion of 0.01-2.0 w/v %. (0023);
surfactants, generally contained in a proportion of 0.005-1.0 w/v %. (0024);
and buffers, generally contained in a proportion of 0.01-2.0 w/v %. (0027).
The buffer should have buffering capacity in the range of pH 5.0-8.5. (0027).
Roflumilast (0020) is one of the optional active agents.
Koenen et al. teach Roflumilast as the active agent for the ophthalmological use to treat of the diseases of the eyes.
With regard to claim 10, Bhutada et al. teach tyloxapol as the surfactant (0024).
With regard to claim 11, Bhutada et al. teach phosphate and citrate buffers (0027) and (0028).
With regard to claim 13, Bhutada et al. teach the suspension (0018).
With regard to claim 14 and 15, Bhutada et al. teach a particle size distribution range, 0.01-100, 0.01-50, 0.01-30, 0.1-20, or 0.01-5.0μm, (Brief manufacturing procedure, Step-C: Preparation of final composition (In aseptic area)).
Claim 17, Bhutada et al. teach “Pharmaceutical Ophthalmic Compositions (0017) comprising:
roflumilast (0020), the active ingredient content may vary depending on type of active, diseases to be treated and the like, preferably 0.005-5.0 w/v %. (0022);
viscosity agents including polyvinylpyrrolidone, is generally present in a composition in a proportion of 0.01-2.0 w/v %. (0023);
surfactants, generally contained in a proportion of 0.005-1.0 w/v %. (0024);
and buffers, generally contained in a proportion of 0.01-2.0 w/v %. (0027).
The buffer should have buffering capacity in the range of pH 5.0-8.5. (0027).
Roflumilast (0020) is one of the optional active agents.
Koenen et al. teach Roflumilast as the active agent for the ophthalmological use to treat of the diseases of the eyes.
With regard to claim 18, Bhutada et al. teach polysorbate as the surfactant in examples 5-7, (0052) – (0054).
With regard to claim 19, Bhutada et al. teach phosphate and citrate buffers (0027) and (0028).
With regard to claim 21, Bhutada et al. teach the suspension (0018).
With regard to claim 22 and 23 Bhutada et al. teach a particle size distribution range: 0.01-100, 0.01-50, 0.01-30, 0.1-20, or 0.01-5.0 μm (Brief manufacturing procedure, Step-C: Preparation of final composition (In aseptic area)).
Claims 8, 16 and 24, are rejected under 35 U.S.C. 103 as being obvious over Bhutada et al. (US 20120283252 A1), in view of Koenen et al. (WO 03099278 Al) and further in view of Mohr et al., (Mohr et al., Gamma irradiation for terminal sterilization of 17 b-estradiol loaded poly-(D,L-lactide-co-glycolide) microparticles, Journal of Controlled Release 61 (1999) 203–217).
The teachings of Bhutada et al. and Koenen et al. in claim 1 are described above.
Bhutada et al. and Koenen et al. do not teach gamma sterilization of Roflumilast.
Mohr et al. teach terminal sterilization method for with gamma-irradiation for parenteral drug delivery system (pdf pg. 1, right col., 1st par.), including determining bioburden of the starting materials (pdf. whole pg. 13, Table 3 and 4) and the active agent 17b-Estradiol stability and degradation under gamma-irradiation at different irradiation doses (kGy) (pdf pg. 8 and pg. 9, Table 2). Mohr et al. teach that with the selected irradiation doses, the active ingredient 17b-Estradiol stabilities are within the range of 94.64%-99.99%.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare the ophthalmic pharmaceutical compositions taught by Bhutada et al., and with the active agent Roflumilast, taught by Bhutadata et al. and Koenen et al. and to carry out the terminal sterilization of parenteral drug delivery system with gamma terminal sterilization and to have the active agent stability up to 99.99% taught by Mohr et al. since it has been proven that it can be done by measuring bioburden and determining the suitable irradiation dose kGy.
Claim 25 is rejected under 35 U.S.C. 103 as being obvious over Bhutada et al. (US 20120283252 A1), in view of Koenen et al. (WO 03099278 Al) further in view of Mohr et al., (Mohr et al., Gamma irradiation for terminal sterilization of 17 b-estradiol loaded poly-(D,L-lactide-co-glycolide) microparticles, Journal of Controlled Release 61 (1999) 203–217).
Bhutada et al. teach a process for preparing an ophthalmic composition comprising a
carbonic anhydrase inhibitor, which comprises a) preparing a slurry comprising an inactive ingredient and a surfactant (claim 1). The active ingredient used in the pharmaceutical ophthalmic composition, may be a PDE-4 inhibitor, such as roflumilast (0020). The buffer should have buffering capacity in the range of pH 5.0-8.5. (0027). In addition, Koenen et al. teach Roflumilast as the active agent for the ophthalmological use to treat of the diseases of the eye.
b) Bhutada et al. teach bulk volume aseptically filled and sealed in unit containers (packaging processes) (Fig 1, pg. 2, last of step-C).
Bhutada et al. and Koenen et al. do not teach sterilization by gamma irradiation.
c) Mohr et al., teach terminal sterilization method for with gamma-irradiation for parenteral drug delivery system (pdf pg. 1, right col., 1st par.).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare the ophthalmic composition taught by Bhutada et al., with an active ingredient Roflumilast and with the pH range taught by Bhutada et al. and Koenen et al., and terminally sterilize the pharmaceutical composition package(s) by gamma irradiation, taught by Mohr, because the methods have been provided to have high stability of the active ingredient. Bhutada et al. have provided all ingredients of ophthalmic compositions. One of ordinary skill in the art would have to work out details.
Double Patenting
The non-statutory 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 non-statutory 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 and 2 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claim 1 and 4, respectively of co-pending Application No. 18/368,832 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both of the claims 1 recite a concentration ophthalmic pharmaceutical composition comprising:
about 2% to about 5% w/v of roflumilast;
a viscosity agent comprising hydroxypropyl methylcellulose;
a surfactant;
a buffer;
and claim 2 of the instant application is identical with claim 4 of the co-pending Application No. 18/368,832 (reference application).
This is a provisional non-statutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
With Regard to 103 rejection:
A. Response to Rejection of Claims 1-3, 5-7, 9-11, 13-15, 17-19, and 21-23:
Applicant argues that the cited art, alone or in combination, fails to teach or suggest the claimed invention.
This argument has been fully considered, but is not found persuasive because Bhutada teaches all ingredients and percentages of ingredients of compositions and in liquid formulations, which applicant is reciting in the claims.
Applicant argues that the cited art references fail to teach or suggest a stability problem (hydrolysis) with ophthalmic roflumilast compositions, let alone the solution to that problem (formulating an ophthalmic roflumilast composition at a certain pH range). Here, the cited art is silent on the problem identified by the inventors. Neither Bhutada nor Koenen teach or suggest that roflumilast compositions are susceptible to hydrolysis. Further, Mohr is only cited in the Office Action with respect to certain claims relating to terminal sterilization. Bhutada also fails to teach or suggest the claimed pH range. Given that Bhutada does not contain any particularized teachings relating to roflumilast, Bhutada fails to teach or suggest the above-discussion problem (i.e., hydrolysis of roflumilast) or the claimed solution (i.e., formulating the composition at a pH of 6.0 to 6.7). Rather, Bhutada only includes a generic disclosure that the pH of the formulation can be essentially any pH value as long as it is nonirritating. A person of ordinary skill in the art would not have arrived at the claimed compositions having the claimed pH values in view of Bhutada.
This argument has been fully considered, but is not found persuasive because Roflumilast is one of the optional active agents, which Bhutada teaches in liquid ophthalmic formulations so Bhutada does not go into detail of Roflumilast and Bhutada teaches the generally acceptable pH for the ophthalmic formulations, pH 5.0-8.5 (0027), which cover the range of pH applicant recites and even though applicant recites the hydrolysis problem of Roflumilast in the Specification, applicant does not recite that problem in the claims. One with skill in the art can learn from and select specific parts of several prior arts’ teachings before the effective filing date of the invention to achieve better outcome results even though some prior arts may teach more and may teach different things. Especially, when one with skill in the art wants to prepare ophthalmic formulation for Roflumilast, they should apply all ingredients taught by Bhutada, and should optimize their percentage, and pH due to Roflumilast hydrolysis problem.
Applicant argues that Koenen fails to remedy the deficiencies of Bhutada. While Koenen does disclose compositions of roflumilast, Koenen, of the exemplary formulations of roflumilast provided in Koenen, many of them are not ophthalmic compositions of roflumilast in liquid formulations. They are in tablets, coated tablets, capsules, suppositories, patches, emulsions, suspensions. Fourteen of the seventeen examples disclosed in Koenen are of tablets to be administered orally.
This argument has been fully considered, but is not found persuasive because the basis for 103 rejection is that no one reference has to teach all the claim limitations for an obviousness rejection and therefore several references are combined to render the claims obvious. Even though Koenen does not teach ingredients and compositions for liquid formulations. Koenen teaches more ingredients and compositions of tablet formulations, Koenen teaches a pharmaceutical preparation comprising roflumilast for treatment of a disease of the eye, and Koenen teaches eye lotions, eye inserts, eye ointments, eye sprays, eye drops. Koenen only support Bhutada in the rejection of claim 1. Claims 2-3, 5-7, 9-11, 13-15, 17-19 and 21-23 are rejected by Bhutada.
Applicant argues that there is evidence of unexpected results supports the patentability of the claimed invention. The Second Gukasyan Declaration supports a finding that the claimed invention produces unexpected and surprising results. The Office Action alleges that "the studied pH range 6.4-6.5 is not reasonably commensurate in scope with the claims of the pH 6.0-6. 7 ."
Examiner Wax indicated that additional data evidencing the unexpected results at both ends of the claimed range would be helpful. The Second Gukasyan Declaration includes experimental data across the claimed pH range, including stability data for formulations reporting a pH of 6.0 and 6.7 range with minimal to undetectable impurity levels. See id., paragraphs 7-11.
This argument has been fully considered, but is not found persuasive because applicant recites limitations of the composition having a pH between 6.0 and 6.7 (Claim 1, 9, 17 and 25), but the 2nd affidavit only provides the stability without high impurities of samples at pH 6.6, even though the pH is changed within the range 6.0-6.7, from 6.6 to 6.0 (pH is reduced 0.6) at the lowest pH, during 12 months. What will happen with samples with pH 6.0-6.5, prepared at t=0? would pH 6.0 be reduced to 5.4, and what would the impurities be when the pH at 5.4? Unless the applicant recites the limitation of a fixed pH 6.6 at t=0 and the variations are within the range of 6.0-6.7. Also, it would be helpful if applicant provides the impurities of roflumilast outside of the pH range 6.0-6.7 to support their claims.
B. Response to Rejections of Claims 8, 16, 24, and 25:
Applicant argues that Mohr fails to remedy the deficiencies of Bhutada and Koenen. Claims 8, 16, and 24 depend from claims 1, 9, and 17, respectively.
This argument has been fully considered, but is not found persuasive because there are not deficiencies of Bhutada and Koenen to remedy and because the applicant’s affidavit brings questions as described above.
Applicant argues that Mohr is cited with respect to claims 8, 16, 24, and 25, which relate to terminal sterilization. Claim 8, 16, and 24 recite that the pharmaceutical composition retains a percentage of greater than 99% roflumilast following terminal sterilization. Claim 25 relates to a method of preparation of a stable ophthalmic formulation involving gamma irradiation. Mohr is directed to gamma irradiation for a different active ingredient and fails to teach or suggest any ophthalmic compositions of roflumilast, let alone with the claimed excipients.
This argument has been fully considered, but is not found persuasive because the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, for claims 8, 16, 24 and 25, it would have been obvious to one with skill in the art to select irradiation doses to maintain the active ingredient high percentage 94.64%-99.99%, as Mohr teaches for the active ingredient 17b-Estradiol.
C. Regard Double Patenting Rejection,
Applicant argues that MPEP § 804.1.B.l(b)(i) provides that when the only remaining rejection is a provisional double-patenting rejection between two pending applications, the rejection should be withdrawn in the earlier-filed application. The present application has an effective filing date of September 20, 2022, while the '832 application has an effective filing date of September 15, 2023.
This argument has been fully considered, but is not found persuasive because this double patenting is not the only remaining rejection!
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NGOC-ANH THI NGUYEN whose telephone number is (571)270-0867. The examiner can normally be reached Monday - Friday 8:00 am.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert A Wax can be reached on 571-272-0623. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/NGOC-ANH THI NGUYEN/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615