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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 09/16/2026 has been entered.
Election/Restrictions
Applicant’s election without traverse of Group (I) with the addition osteoarthritis as the elected subject suffering from a disease species and the inflammation or pain species, knees, and solution as the dosage form in the reply filed on 11/03/2025 is acknowledged and maintained.
Priority
This application is the U.S. national stage application, under 35 U.S.C. § 371, of
International Patent Application No. PCT/CN2021/098323, filed on June 4, 2021, which claims the benefit and priority of International Patent Application No. PCT/CN2020/094560, filed on June 5, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/16/2026 has been considered by the examiner.
Claim Status
. Claims 4-6, 14-16, 18, 22-30 are pending. Claims 1-3, 7-13, 17, and 19-21 are canceled. Claims 4-6, 14-16, 18, 21-30 are examined in accordance to the elected species.
Action Summary
The rejection of claim 21 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is withdrawn in view of the cancellation of claim 21.
The rejection of claims 4-6, 14-16, 18, and 21-30 under 35 U.S.C. 103 as being unpatentable over Yu et al (US9,872,846 B2) in view of Argoff et al (Ther Clin Risk Manag. 2011 Sep 20; 7:393–399) has been considered but are moot. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Yu et al. and King-Smith et al.
The rejection of claims 4-6, 14-16, 18, and 21-30 on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 9,872,846 B2 in view of Yu et al (US9,872,846 B2) and Argoff et al (Ther Clin Risk Manag. 2011 Sep 20; 7:393–399.) has been considered but are moot. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Yu et al. and King-Smith et al.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 nonobviousness.
Claims 4-6, 14-16, 18, and 22-30 are rejected under 35 U.S.C. 103 as being unpatentable over Yu et al (US9,872,846 B2) in view of King-Smith et al. (US8,470,886 B2) and Yildirim et al. (WO2016/137411 A1).
Yu teaches methods for treating an ibuprofen-treatable condition, including pain and inflammation by transdermally administering a pharmaceutical composition comprising a therapeutically effective amount of an high penetration prodrug (HPP) of a non-steroidal anti-inflammatory agent (NSAIA ). See claim 1. Yu’s claim 10 specifically encompasses diethylaminoethyl 2-(ρ-isobutylphenyl) propionate
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, i.e., the compound presently claimed, including pharmaceutically acceptable salts thereof. Yu further teaches the localized administration is desirable for treatment of pain and inflammation because administration at the site of pain or injury permits delivery the action site while reducing systemic exposure. See col. 1, discussion of localized/transdermal administration. Claim 6 of Yu discloses a human subject.
Yu explains that its HPPs may be locally delivered to the action site at high concentration due to their ability to penetrate biological barriers, thereby reducing the need for systemic administration. See col. 1; background Section. Yu teaches that pharmaceutical compositions containing its HPPs may be administered topically or transdermally, that the concentration of HPP in such formulation may “vary widely,” and, significantly, that concentration is selected based upon factors including fluid volume, viscosity, body weight, the particular mode of administration, and the biological system’s needs and provides exemplary concentrations including 0.1-99.5%, 10-70%, and 5-20% by weight. See col. 76, ll. 18-24.
Yu additionally provides experimental evidence specifically demonstrating transdermal administration of the presently claimed ibuprofen prodrug, In connection with Fig. 3c, Yu teaches administration of diethylaminoethyl 2-(p-isobutylphenyl) propionate AcOH (DEAE-IBPP) orally and transdermally and measures prolongation of the pain threshold, thereby demonstrating analgesic activity of the compound following transdermal administration. See Fig. 3c and accompanying description. Yu separately demonstrates anti-inflammatory activity of the same compound, In connection with Fig. 4c, Yu teaches transdermal administration of DEAE-IBPP in the carrageenan-induced swelling model and measures inhibition of swelling. See Fig. 4c and accompanying description.
Thus, Yu taches the presently claimed compound, topical/transdermal, administration thereof, and its successful use to provide analgesic and anti-inflammatory effects.
Yu does not expressly teach administration to a human subject at the presently claimed amount of about 1 mg to about 80 mg per day per site.
King-Smith teaches topical ibuprofen formulations and methods of using such formulations for topical treatment of pain. See col. 1, lines corresponding to Field and Background, explaining that ibuprofen is an NSAID used for arthritis and analgesia, particularly where an inflammatory component is present.
King-Smith expressly teaches applying an effective amount of a topical ibuprofen composition to skin of a subject for treatment of pain, including pain associated with inflammation and osteoarthritis. Most significantly, King-Smith teaches that its topical compositions permit delivery of an ibuprofen daily dosage of:
about 0.01-1200 mg;
about 0.1-400 mg;
about 1-370 mg;
about 5-350 mg;
about 10-300 mg; or
about 100-250 mg, in a single or divided dose. See col. 9-10.
Thus, King-Smith expressly teaches a topical NSAID daily dosage range beginning at about 1
mg which overlaps the presently claimed range of about 1-80 mg/day. Where claimed and prior art ranges overlap, such overlap supports a prima facie case of obviousness. MPEP §2144.05(I).
King-Smith moreover expressly connects dosage with the particular treatment area. King-Smith teaches that the concentration may be selected such that the dose is administered one to four times daily over specific skin areas and expressly states that “the dosage and application area will vary on, and can be tailored to, the area being treated.” See col. 10. King-Simth further teaches that, in osteoarthritis, delivery of the active agent to tissues surrounding the affected joint may be necessary for therapeutic benefit and teaches local or regional delivery into tissues underlying the skin while minimizing systemic distribution. See col. 6.
King-Smith expressly identifies osteoarthritis and chronic joint diseases involving the knee, elbow, hand, wrist, and hip, as well as muscle pain, lower-back pain, neck pain, rheumatoid arthritis, fibromyalgia, and gout, as conditions/sites for treatment using its topical ibuprofen compositions. See col. 18.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer Yu’s known, topical/transdermallly active ibuprofen prodrug to an affected site of a human subject using a daily amount within the overlapping topical NSAID dosage taught by King-Smith, including an amount within about 1-80 mg/day/site.
One would have been motivated to do so because Yu expressly teaches that DEAE-IBP is suitable for topical/transdermal administration and experimentally demonstrates analgesic and anti-inflammatory activity following transdermal administration, while King-Smith teaches that topical ibuprofen therapy is useful for pain and inflammation, including osteoarthritis, and expressly teaches that tailoring the daily dose and application are to the area being treated, Moreover, King-Smith expressly teaches that an “effective amount” depends upon the desired therapeutic result and states that, once the desired effect is known, determining an effective amount within the skill of the ordinary skilled artisan. See col. 6. Accordingly, one of ordinary skill in the art would have had reason to select and optimize Yu’s topical amount within the overlapping daily dosage range taught by King-Smith according to the particular affected site, with a reasonable expectation of successfully treating pain and/or inflammation because Yu itself demonstrates analgesic and anti-inflammatory activity following transdermal administration of the identical compound, and King-Smith establishes that topical NSAID dose and application are parameters tailored to the treatment site.
Regarding claims 5, 6, and 14-16, King-Smith further establishes that the amount of topical NSAID delivered, the area of application, and skin penetration are known parameters of topical treatment. King-Smith teaches that various factors affect topical absorption and penetration including the active ingredient, vehicle, pH. Solubility, spreadability, membrane permeability, and formulation characteristics. See col. 1-2. King-Smith also expressly teaches daily topical ibuprofen amounts beginning at about 0.001 mg and including ranges of 1-370 mg and 5-350 mg in single or divided doses, while teaching that dosage and application area are tailored to the area being treated.
Yu likewise teaches that formulation concentration varies according to such considerations as fluid volume, body weight, mode of administration, and biological-system needs.
Accordingly, selection of the particular dose-per-area and dose-per-site amounts recited by claims 5, 6, and 14-16 would have represented selection of workable amounts within the known topical dosing regimen through routine optimization of parameters known to affect topical delivery and therapeutic effect.
Regarding claim 18, King-Smith expressly teaches topical treatment of pain associated with osteoarthritis and additionally identifies rheumatoid arthritis, muscle pain, fibromyalgia, and gout among the disorders treated using its topical ibuprofen compositions. King-Smith further identifies joints including the knee, elbow, hand, wrist, and hip. See col. 18.
Accordingly, selection of any one of these expressly taught pain-inflammatory conditions would have been obvious for the reasons discussed above.
Regarding claim 22, King-Smith teaches its topical ibuprofen composition may be formulated as spray, gel, cream, emulsion, microemulsion, lotion, ointment, solution, or transdermal patch, among other topical forms. See col. 14. King-Smith again identifies a spray, cream, emulsion, microemulsion, gel, lotion, ointment, solution, and transdermal patch in its formulation discussion.
Regarding claim 23, Yu teaches pharmaceutically acceptable carriers including aqueous carriers and polar solvents such as acetone, and alcohol, and teaches topical/transdermal administration. King-Smith likewise teaches hydroalcoholic topical formulations and specifically identifies ethanol, and isopropanol suitable alcohols.
Thus, the claimed topical dosage forms and alcohol-containing solutions would have been obvious choices among the topical formulations expressly taught by the combined references.
Regarding claim 24, King-Smith teaches topical ibuprofen compositions containing approximately 0.1-10% w/w, including approximately 1-8%, 2-7%, 3-6.5%, 4-6%, and approximately 5% ibuprofen. Yu independently teaches that the concentration of its HPP formulations may vary widely and expressly identifies exemplary concentrations of 0.1-99%, 10-70%, and 5-20% by weight, with concentration selected according to fluid volume, mode of administration, and biological system needs.
Accordingly, concentration is expressly recognized by both references as a parameter associated with topical delivery, and optimization of concentration to provide the desired dose in a convenient application volume would have been within ordinary skill.
Regarding claims 25-27, King-Smith expressly teaches that its topical ibuprofen dosage may be administered in single or divided doses, and that concentration may be selected to permit application one to four times daily. See col. 9. King-Smith further teaches dispensing its composition from a reservoir using a release assembly, such as pump head, which may be metered to dispense a consistent amount of formulation, and teaches containers containing one or more unit dosage forms. See col. 18-19.
Thus, providing Yu’s topical composition in a unit dose and selecting a suitable unit volume/amount to deliver the desired topical dose would have been a predictable implementation of the known topical therapy.
For claim 26, King-Smith’s express teaches topical ibuprofen daily dosage range beginning at about 0.1 mg, 0.1 mg, 1 mg, and 5 mg in single or divided doses and further teaches selecting concentration to permit application to one to four times daily. Accordingly, selection of a unit dose within the presently claimed range of about 0.1 mg to about 8 mg would have represented routine selection of the amounts per administration within King-Smith’s expressly taught low-milligram topical dosing regimen.
Regarding claim 28, King-Smith expressly teaches administration three times daily, twice daily, or once daily. See col. 18. These expressly taught frequencies fall within claimed 28.
Regarding claim 29, King-Smith’s express teaching of once-daily administration corresponds to administration once every 24 hours, which is expressly encompassed by claim 29.
Regarding claim 30, King-Smith teaches treatment of both acute and chronic pain. It further explains that treatment may comprise a single administration or a series of applications; treatment duration depends upon factors including severity, patient age, concentration and activity of the composition; dosage may change over the course of treatment; and chronic administration may be required. See col. 8.
Thus, administering the topical therapy for the duration necessary to treat the condition, including repeated or chronic administration, would have been obvious from King-Smith’s express teaching.
Applicant’s arguments and Response to Applicant’s arguments
Acknowledgement is made of the receipt and entry of Applicant’s arguments/remarks filed on September 16, 2026.
Applicant’s arguments have been considered but are not persuasive of patentability in view of the rejection as presently set forth.
Applicant argues, inter alia, that the dosage disclosure previously relied upon in view of Yu et al. at col. 76 is directed to intravenous administration and therefore does not establish the presently claimed topical dosage of about 1 mg to about 80 mg per day per site. Applicant further argues that Yu’s reported skin-penetration rate does not constitute an administered dosage because penetration rate does not constitute and an administered dosage because penetration or flux is distinct from the amount applied.
In response, these arguments have been considered. The present rejection, however, does not rely upon Yu’s intravenous dosage disclosure or penetration rate as establishing the presently claimed topical daily dosage. Rather, King-Smith et al. expressly teach topical ibuprofen formulation for treatment of pain, including pain associated with inflammation and osteoarthritis. See col. 1, ll. 19-22; col. 3, II. 1-15, King-Smith further expressly teaches that the topical composition permits delivery of an ibuprofen daily dosage of about 0.01-1200 mg, about 0.1-400 mg, about 1-370 mg., about 5-350 mg, about 10-325 mg, about 50-300 mg, or about 100-250 mg, in single or divided doses. Thus, King-Smith expressly teaches a topical daily dosage range that overlaps the presently claimed range of about 1-80 mg/day. King-Smith additionally teaches that the concentration may be selected such that the dosage is provided by application one to four times per day, including one to two times per day, to a selected skin area, and expressly states that “the dosage and application area will vary on, and can be tailored to, the are being treated.” See col. 9, II. 15-29.
Accordingly, the prior art does not merely disclose an untreated systemic dosage and require speculation as to an appropriate topical dose. Rather, King-Smith expressly relates to daily topical dosage to the particular area being treated.
Applicant also argues that one of ordinary skill would not have been motivated to substantially reduce the dosage taught by Yu and would not have reasonably expected such reduced dosage to remain therapeutically effective.
In response, this argument is not persuasive because it considers Yu in isolation and does not address teachings of the references as presently combined. Simth-King expressly teaches low-milligram daily topical ibuprofen dosages encompassing the claimed dosage and further teaches that an “effective amount” is an amount sufficient to achieve the desired result and that, once the desired result is known, determination of an effective amount is within the skill of the ordinary skilled artisan. See col. 5, II. 39-44. Moreover, Smith-King expressly teaches localized topical treatment of osteoarthritis and explains that delivery of active agent to tissues surrounding the joint may be necessary to achieve therapeutic benefit while local delivery can minimize systemic distribution. See col. 6, II. 26-43. King-Smith further identifies osteoarthritis and chronic joint disorders involving, inter alia, the knee, elbow, hand, wrist, and hip, as conditions/site suitable for its topical ibuprofen treatment. See col. 18, II. 32-50.
Thus, the prior art expressly provides both a reason to administer a topical NSAID locally to an affected joint and guidance concerning the amount, frequency, and treatment area.
Applicant’s arguments concerning differences physiochemical properties among different NSAIDs likewise do not overcome the rejection. Yu is relied upon for the presently claimed (diethylamino)ethyl 2-(4-isobutylphenyl) propionate compound and itself demonstrates successful transdermal administration of that ibuprofen prodrug and its analgesic and anti-inflammatory activity. For example, Yu reports transdermal administration of DEAE-IBPP.AcOH in its pain-threshold experiment (Fig. 3c) and separately in its carrageenan-induced inflammation experiment (Fig. 4c). Thus, the rejection does not depend upon an assumption that the topical-delivery properties of a chemically different NSAID would necessarily be shared by the claimed compound.
Applicant further relies upon the Phase-2 clinical studies disclosed in the specification and argues that the claimed reduced dosage produced unexpected therapeutic results, including results obtained at doses of 8.75 mg, 17.5 mg, and 35 mg and comparisons with celecoxib and oral ibuprofen.
The evidence has been considered but is not persuasive of non-obviousness over the prior art as a whole.
First, the asserted results establish efficacy at particular tested doses and under particular clinical conditions, but do not establish criticality of the claimed range of about 1 mg to about 80 mg per day per site. In particular, Applicant has not established that the endpoints of approximately 1 mg and 80 mg are critical or that substantially the entire breadth of the claimed range produces the asserted unexpected results.
Second, the asserted comparison with celecoxib and orally administered ibuprofen does not establish that the claimed dosage produces unexpected restuls relative to the most pertinent prior-art teachings concerning topical NSAID administration. King-Smith expressly teaches topical ibuprofen daily dosages beginning at about 1 mg and expressly teaches tailoring dosage and application area to the area being treated. Yu expressly teaches the claimed compound, the claimed topical administration, the claimed condition, and the claimed subject, Thus, the low-milligram topical NSAID and topical administration of the claimed compound were contemplated by the prior art references in combination. Furthermore, to the extent Applicant relies upon results obtained using a topical spray formulation, topical NSAID spray administration at low milligram amounts was also known. Yildirim et al. expressly teaches topical spray compositions for treatment of pain and teaches formulations containing 1-20 mg ibuprofen, preferably 5 mg. See p. 3. Thus, the evidence does not establish that administration of a topical NSAID by sprat at low-milligram amounts was itself unexpected. The Office does not dispute that Applicant’s clinical studies demonstrate therapeutic activity of particular embodiments of the claimed method. However, the evidence that particular embodiments are clinically effective is not, without more, sufficient to establish that the claimed dosage range as a whole represents an unexpected departure from the prior art, particularly where the prior art expressly teaches overlapping topical daily NSAID dosages, tailoring dosage to the treatment area, localized treatment of osteoarthritis and affected joints, and low-milligram topical spray administration.
Accordingly, Applicant’s argument and evidence have been fully considered but do not overcome the prima facie case of obviousness established by the references as presently applied.
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 nons-tatutory 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 4-6, 14-16, 18, and 22-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 9,872,846 B2 in view of King-Smith et al. (US8,470,886 B2) and Yildirim et al. (WO2016/137411 A1).
Although the claims at issue are not identical, they are not patentably distinct from each other.
The U.S. patent claims teach a method for treating an ibuprofen-treatable condition in a subject in need thereof comprising:
transdermally administering to the subject a pharmaceutical composition,
wherein the ibuprofen-treatable condition is selected from fever, pain, and inflammation; and
wherein the pharmaceutical composition comprises a therapeutically effective amount of at least one compound of Structure 1:
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or stereoisomers thereof. (See claim 10) Moreover, the U.S. patent claims teach the condition treatable by Ibuprofen is rheumatoid arthritis or osteoarthritis and the composition is formulated as a solution, suspension, spray, lotion, emulsion or a gel, and the subject is a human subject. (See claims 2-6.) The compound is
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. (See claim 10.) This compound is the same as the compound claimed.
The U.S. patent claims do not expressly teach administration to a human subject at the presently claimed amount of about 1 mg to about 80 mg per day per site.
King-Smith teaches topical ibuprofen formulations and methods of using such formulations for topical treatment of pain. See col. 1, lines corresponding to Field and Background, explaining that ibuprofen is an NSAID used for arthritis and analgesia, particularly where an inflammatory component is present.
King-Smith expressly teaches applying an effective amount of a topical ibuprofen composition to skin of a subject for treatment of pain, including pain associated with inflammation and osteoarthritis. Most significantly, King-Smith teaches that its topical compositions permit delivery of an ibuprofen daily dosage of:
about 0.01-1200 mg;
about 0.1-400 mg;
about 1-370 mg;
about 5-350 mg;
about 10-300 mg; or
about 100-250 mg, in a single or divided dose. See col. 9-10.
Thus, King-Smith expressly teaches a topical NSAID daily dosage range beginning at about 1
mg which overlaps the presently claimed range of about 1-80 mg/day. Such an overlapping range provides evidence that selection of the presently claimed dosage would have been obvious variation of the invention defined by the patent claims. See MPEP §2144.05(I).
King-Smith moreover expressly connects dosage with the particular treatment area. King-Smith teaches that the concentration may be selected such that the dose is administered one to four times daily over specific skin areas and expressly states that “the dosage and application area will vary on, and can be tailored to, the area being treated.” See col. 10. King-Simth further teaches that, in osteoarthritis, delivery of the active agent to tissues surrounding the affected joint may be necessary for therapeutic benefit and teaches local or regional delivery into tissues underlying the skin while minimizing systemic distribution. See col. 6.
King-Smith expressly identifies osteoarthritis and chronic joint diseases involving the knee, elbow, hand, wrist, and hip, as well as muscle pain, lower-back pain, neck pain, rheumatoid arthritis, fibromyalgia, and gout, as conditions/sites for treatment using its topical ibuprofen compositions. See col. 18.
Yildirim et al. expressly teaches topical spray compositions for treatment of pain and teaches formulations containing 1-20 mg ibuprofen, preferably 5 mg. See p. 3.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer the patent claims’ known, topical/transdermallly active ibuprofen prodrug to an affected site of a human subject using a daily amount within the overlapping topical NSAID dosage taught by King-Smith, including an amount within about 1-80 mg/day/site.
One would have been motivated to do so because the patent claims expressly teach that the compound is suitable for topical/transdermal administration for treatment of pain and inflammation, while King-Smith teaches that topical ibuprofen therapy is useful for pain and inflammation, including osteoarthritis, and expressly teaches that tailoring the daily dose and application are to the area being treated, Moreover, King-Smith expressly teaches that an “effective amount” depends upon the desired therapeutic result and states that, once the desired effect is known, determining an effective amount within the skill of the ordinary skilled artisan. See col. 6. Accordingly, one of ordinary skill in the art would have had reason to select and optimize Yu’s topical amount within the overlapping daily dosage range taught by King-Smith according to the particular affected site, with a reasonable expectation of successfully treating pain and/or inflammation because the patent claims themselves recite transdermal administration of the identical compound for treatment of paint and inflammation, while King-Smith establishes that topical NSAID dose and application are parameters tailored to the treatment site.
Regarding claims 5, 6, and 14-16, King-Smith further establishes that the amount of topical NSAID delivered, the area of application, and skin penetration are known parameters of topical treatment. King-Smith teaches that various factors affect topical absorption and penetration including the active ingredient, vehicle, pH. Solubility, spreadability, membrane permeability, and formulation characteristics. See col. 1-2. King-Smith also expressly teaches daily topical ibuprofen amounts beginning at about 0.001 mg and including ranges of 1-370 mg and 5-350 mg in single or divided doses, while teaching that dosage and application area are tailored to the area being treated.
Accordingly, selection of the particular dose-per-area and dose-per-site amounts recited by claims 5, 6, and 14-16 would have represented selection of workable amounts within the known topical dosing regimen through routine optimization of parameters known to affect topical delivery and therapeutic effect.
Regarding claim 18, King-Smith expressly teaches topical treatment of pain associated with osteoarthritis and additionally identifies rheumatoid arthritis, muscle pain, fibromyalgia, and gout among the disorders treated using its topical ibuprofen compositions. King-Smith further identifies joints including the knee, elbow, hand, wrist, and hip. See col. 18.
Accordingly, selection of any one of these expressly taught pain-inflammatory conditions would have been obvious for the reasons discussed above.
Regarding claim 22, King-Smith teaches its topical ibuprofen composition may be formulated as spray, gel, cream, emulsion, microemulsion, lotion, ointment, solution, or transdermal patch, among other topical forms. See col. 14. King-Smith again identifies a spray, cream, emulsion, microemulsion, gel, lotion, ointment, solution, and transdermal patch in its formulation discussion.
Regarding claim 23, King-Smith teaches pharmaceutically acceptable carriers including aqueous carriers and polar solvents such as ethanol. King-Smith also teaches hydroalcoholic topical formulations and specifically identifies ethanol, and isopropanol suitable alcohols.
Thus, the claimed topical dosage forms and alcohol-containing solutions would have been obvious choices among the topical formulations expressly taught by the combined references.
Regarding claim 24, King-Smith teaches topical ibuprofen compositions containing approximately 0.1-10% w/w, including approximately 1-8%, 2-7%, 3-6.5%, 4-6%, and approximately 5% ibuprofen.
Accordingly, concentration is expressly recognized by both references as a parameter associated with topical delivery, and optimization of concentration to provide the desired dose in a convenient application volume would have been within ordinary skill.
Regarding claims 25-27, King-Smith expressly teaches that its topical ibuprofen dosage may be administered in single or divided doses, and that concentration may be selected to permit application one to four times daily. See col. 9. King-Smith further teaches dispensing its composition from a reservoir using a release assembly, such as pump head, which may be metered to dispense a consistent amount of formulation, and teaches containers containing one or more unit dosage forms. See col. 18-19.
Thus, providing Yu’s topical composition in a unit dose and selecting a suitable unit volume/amount to deliver the desired topical dose would have been a predictable implementation of the known topical therapy.
For claim 26, King-Smith’s express teaches topical ibuprofen daily dosage range beginning at about 0.1 mg, 0.1 mg, 1 mg, and 5 mg in single or divided doses and further teaches selecting concentration to permit application to one to four times daily. Accordingly, selection of a unit dose within the presently claimed range of about 0.1 mg to about 8 mg would have represented routine selection of the amounts per administration within King-Smith’s expressly taught low-milligram topical dosing regimen
Regarding claim 28, King-Smith expressly teaches administration three times daily, twice daily, or once daily. See col. 18. These expressly taught frequencies fall within claimed 28.
Regarding claim 29, King-Smith’s express teaching of once-daily administration corresponds to administration once every 24 hours, which is expressly encompassed by claim 29.
Regarding claim 30, King-Smith teaches treatment of both acute and chronic pain. It further explains that treatment may comprise a single administration or a series of applications; treatment duration depends upon factors including severity, patient age, concentration and activity of the composition; dosage may change over the course of treatment; and chronic administration may be required. See col. 8.
Thus, administering the topical therapy for the duration necessary to treat the condition, including repeated or chronic administration, would have been obvious from King-Smith’s express teaching.
Applicant’s arguments directed to the nonstatutory double patenting rejection have been fully considered but are not persuasive. Applicant traverses the rejection for substantially the same reasons presented with respect to the rejection under 35 U.S.C. §103. Those arguments, including Applicant’s contentions concerning the claimed dosage amount, motivation to employ the dosage amount, reasonably expectation of success, and alleged unexpected results, have been full addressed above and are incorporated herein by reference.
Conclusion
Claims 4-6, 14-16, 18, and 22-30 are not allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEAN P CORNET whose telephone number is (571)270-7669. The examiner can normally be reached Monday-Thursday from 7.00am-5.30pm.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
