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 .
Priority
The present application is the U.S. National Stage Application, pursuant to 35 U.S.C. 371, of PCT International Application No. PCT/US2020/047551, filed August 22, 2020, which claims priority to U.S. App. No. 62/890,517, filed August 22, 2019.
Status of the Claims
Claim 5 is cancelled. Claim 1 is amended to incorporate the limitations of claim 5. Claims 1-4, 8-10, 12-13, 15 and 17-20, 23, 25-27 and 31 are pending and are the subject of the Office Action below.
Claim Rejections - 35 USC § 102 Overcome by Amendment
Applicant has amended Claim 1 to a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients, carriers, and/or diluents and one or more non-steroidal anti-inflammatory drugs (NSAID), wherein the total concentration of NSAIDs is less than 75 mg/ml, wherein the total NSAID content of said composition is more than 90% or more than 95% or more than 99% salicylate and derivatives thereof by weight of the NSAID content.
Although the applicant still allows for “one or more” NSAIDs to be a component of the combination at less than 75 mg/mL, they have amended the combination to read on salicylate and derivatives and Radkova et al. J of Pain Research IO (2017): 1592-1600 (Radkova) does not specifically teach the NSAID salicylate, but rather Flurbiprofen.
Claim 4 depends from amended claim 1 wherein the total concentration of NSAIDs is less than 20 mg/ml.
Accordingly, the rejection of claims 1 and 4 are withdrawn.
Claim Rejections - 35 USC § 103 Rejections Maintained
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.
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.
Claims 1-5 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Bouroubi et.al., Pain relief of sore throat with a new anti-inflammatory throat lozenge, ibuprofen 25 mg: A randomised, double-blind, placebo-controlled, international phase III study, Int J Clin Pract. 2017;71: e12961 and in view of Radkova, et.al., Efficacy of flurbiprofen 8.75 mg delivered as a spray or lozenge in patients with sore throat due to upper respiratory tract infection: a randomized, non-inferiority trial in the Russian Federation, Journal of Pain Research 2017:10 1591–1600 and Rathod, et.al., Medicated Lozenges as an Easy to Use Dosage Form, World Journal of Pharmaceutical Research, Volume 7, Issue 16, 2018, 305-322.
Response to Applicants’ Arguments
Applicant argues, regarding claim 1, that although Bouroubi teaches that "oral analgesics such as acetaminophen, aspirin or ibuprofen have been widely used to treat acute sore throat"; Bouroubi does not "does not explicitly disclose the volume of the lozenge," but relies on Rathod's disclosure that lozenges are "typically formulated between a total mass of 1.5 g to 4.5 g" to conclude that a person of ordinary skill in the art would have had "a reasonable expectation of success in arriving at the NSAID composition of less than 75 mg/mL." Applicant then purports that the amended claim remedies the case of obviousness.
Further, regarding claim 5, applicant argues “that rationale at most identifies different NSAIDs used for sore throat treatment. It does not identify an art-based reason to select a salicylate-dominant NSAID composition, much less one in which more than 90% of the total NSAID content is salicylate and derivatives thereof by weight of the NSAID content. There is no basis, whatsoever, to contend that the presently claimed composition is taught or suggested by these references, and even if it were (which Applicant does not concede), there is no basis to contend that the claimed composition would have been though(t) to have any efficacy.”
Contrary to the applicants’ arguments, Radkova does teach a single NSAID in a lozenge form and that the concentration of the NSAID is 100% of Flurbiprofen; 8.75 mg delivered as a spray or lozenge. Although the volume of the lozenge is not disclosed in Radkova, the amount of the NSAID delivered in the volume limitations set forth by Rathod of the tablet as between 1.5 and 4.5 grams is significant. Since the standard cough drops/lozenge are primarily composed of hard sugar/sucrose/sweeteners and corn syrup, their density is slightly higher than water (roughly 1.5 g/cm³), meaning a 4.5-gram lozenge takes up a volume of about 3 mL to 3.5 mL. Radkova used 8.75 mg of Flurbiprofen delivered in a lozenge weight between 1.5 and 4.5 grams as identified by Rathod. Assuming the same density of the lozenge for both the instant application and Radkova, the mg/mL concentration at the smallest possible lozenge volume of 1.5 grams (the highest possible concentration of the NSAID) can be determined as follows:
1.5 gram lozenge (assuming volume of 3.5 mL) = 1.7 mL volume equates to 5.5 mg/mL NSAID; Flurbiprofen.
1.5 gram lozenge (assuming volume of 3.0 mL) = 1.0 mL volume equates to 8.75 mg/mL NSAID; Flurbiprofen.
Further, Bouroubi does teach NSAIDS, including aspirin (salicylate) which have been widely used to treat an acute sore throat and that among these treatments, lozenges provide the most effective treatment because they deliver the longest availability to the affected area and therefore is more targeted and longer delivery of the oral anangesics.
The applicant seems to be replacing the NSAID of Flurbiprofen with NSAID of aspirin (salicylate) in a lozenge form as taught by the combination of Bouroubi, Radkova and Rathod as detailed above.
Applicants’ arguments are not compelling.
35 USC § 103 Rejections Reiterated
Applicants purport a pharmaceutical composition that includes a total concentration of NSAIDs to be used to in a concentration less than 75 mg/mL (as in claim 1) and that the NSAID in the specification is identified as a salicylate derivative that includes acetylsalicylic acid (aspirin) [49] and [50] as in (claim 2), with a total concentration less than 10 mg/ml (as in claim 3) and one or more NSAIDs with a total concentration less than 20 mg/ml (as in claim 4) and a total NSAID concentration of salicylate of more than 90% 95%, to 99% by weight (as in claim 5) delivered as a lozenge (as in claim 13) and a lozenge comprising 0.1 to 10 mg of acetylsalicylic acid; aspirin (as in claim 15).
Claim 1
Bouroubi teaches how the art has used NSAIDs, including acetaminophen, aspirin, and ibuprofen in an oromucosal form for the treatment of sore throat:
“Oral analgesics such as acetaminophen, aspirin or ibuprofen have been widely used to treat acute sore throat. Low-dose topical forms, more appropriate for such a local indication, have been developed. Among these, lozenges provide the highest deposition and longest availability of the active compound in the pharyngeal cavity. Locally delivered NSAIDs for sore throat are available.”
Bouroubi, page 2, column 2 (emphasis added), and describes his goal of making oral lozenges of ibuprofen over systemic modes of administration:
“However, the main limitations of the systemic therapies are the risk of causing systemic adverse reactions whereas the concentration of the drug substance in the target tissue is low.7 To address these issues, an ibuprofen lozenge to be sucked has been developed at the low dose of 25 mg selected from an unpublished dose-range study. Compared with other locally acting forms such as throat sprays and
rinses, the lozenge pharmaceutical form provides a more targeted and longer delivery and hence is more suitable in the management of sore throat.7-9 The lozenge form is available for a variety of active ingredients for treating sore throat,9 but not for ibuprofen, despite its demonstrated efficacy for sore throat relief when administered orally.”
Bouroubi, page 2, column 1, paragraph 2 (emphasis added).
While Bouroubi teaches certain aspects of his 25 mg ibuprofen lozenge, and references other lozenge non-patent literature publications, he does not explicitly disclose the volume of the lozenge (i.e., the 25 mg/mL density limitation). However, one of ordinary skill in the art would have a reasonable expectation of success in arriving at a 25 mg/mL ibuprofen lozenge from the teaching of Bouroubi because, lozenges are generally prepared in the mass range of 1.5 g to 4.5g, and with excipients having an overall density in the range 1.2 g/mL to 1.5 g/mL would lead to Bouroubi’s lozenge meeting the density of claim 1. For example, see the teaching of Ashwini.
Rathod teaches that lozenges are typically formulated between a total mass of 1.5 g to 4.5 g and a size of about 5/8- 3/4 inch, and use many different excipients along to carry the active agent:
“Hard candy lozenges are mixtures of sugar and other carbohydrates in an amorphous (noncrystalline) or glassy state. They can also be regarded as solid syrups of sugars. The moisture content and weight of hard candy lozenge should be between, 0.5 to 1.5% and 1.5-4.5g respectively. These should undergo a slow and uniform dissolution or erosion over 5- 10 min., and should not disintegrate. The temperature requirements for their preparation is usually high hence heat labile materials cannot be incorporated in them.
Rathod, page 310-311, Hard candy lozenges, (emphasis added),
And:
“The lozenge tablets differ from conventional tablets in terms of organolepticity, non-disintegrating characteristics and slower dissolution profiles. The lozenge is made usingheavy compression equipment to give a tablet that is harder than usual, as it is desirable for the troche to dissolve slowly in mouth. They are usually flat faced with sizes, weight, hardness, and erosion time ranging between, 5/8-3/4-inch, 1.5-4 g, 30-50 kg inch2 and 5-10 min, respectively.”
Rathod, page 309 (emphasis added).
Rathod also teaches a vast array of excipients that would be used to prepare the pharmaceutical form of the lozenge.
Although Bouroubi teaches how the art has used NSAIDs including acetaminophen, aspirin, and ibuprofen (with a density limitation of concentration of 25 mg/mL), in an oromucosal form for the treatment of sore throat; including lozenges, they don’t teach the density of the of the lozenge. Rathod teaches that lozenges are typically formulated between a total mass of 1.5 g to 4.5 g and a size of about 5/8- 3/4 inch, and use many different excipients along to carry the active agent. However, one of ordinary skill in the art would have a reasonable expectation of success in arriving at the NSAID composition of less than 75 mg/mL of the instant claim because a 25mg/mL density of the NSAID, ibuprofen, in a lozenge form is taught by Bouroubi and is clearly less than the instant claim. The average lozenge has an average total mass of between 1.5 and 4.5 grams including a range of the excipients, lubricants, binders, coloring and flavoring agents, and humectants as taught by Rathod.
Accordingly, claim 1 is rejected.
Claim 2 limits claim 1, and further requires the NSAID to be aspirin. Although Bouroubi does not exemplify aspirin as the lozenge active agent, he clearly suggests that aspirin could be used as the pharmaceutical active.
Accordingly, claim 2 is rejected.
Claim 4 limits claim 1 to total concentration of NSAIDs is less than 20 mg.
Radkova teaches the efficacy of the NSAID, flurbuprofen, at a concentration of 8.75 mg administered via a lozenge or a spray to treat patients with a sore throat caused by an upper respiratory tract infection in a randomized, multicenter trial of 440 adults with a recent-onset, moderate-to-severe sore throat due to URTI.:
“Flurbiprofen is a non-steroidal anti-inflammatory drug (NSAID) with proven analgesic and anti-inflammatory effects,18,19 and lozenges containing 8.75 mg flurbiprofen have been shown to be safe and effective in relieving the symptoms of a sore throat (including pain).3,20–24 Flurbiprofen 8.75 mg lozenges are available over-the-counter in many countries, and they are the only formulation of flurbiprofen currently available in Russia.”
Radkova, page 1592, paragraph 4 (emphasis added).
“Flurbiprofen 8.75 mg delivered as a spray or lozenge provides effective relief from the pain associated with sore
throats due to URTI. Non-inferiority of the spray versus the
lozenge formulation was established, and both formulations
demonstrated comparable efficacy and safety profiles.”
Radkova, page 1598, Conclusion (emphasis added).
Bouroubi teaches that NSAIDs include oral analgesics such as acetaminophen, aspirin or ibuprofen that have been widely used to treat an acute sore throat and that low dose topical forms have been developed. They also teach that among these, lozenges provide the highest deposition and longest availability of the active compound in the pharyngeal cavity. Locally delivered NSAIDs for sore throat are available. They also teach that an oromucosal form of ibuprofen at a dose of 25 mg/ml is effective at treating an acute sore throat in a Phase III clinical study. Radkova teaches that a different NSAID, Flurbiprofen is delivered via a lozenge or spray to treat a sore throat due to an upper respiratory tract infection at a concentration of 8.75 mg/ml. The concentration of these NASAIDs identified by Bouroubi and Radkova are delivered as 100% of the composition of the lozenge (with unspecified other excipients/components to prepare the drug for delivery as a lozenge) and do not detail a combination of the NSAIDs.
Accordingly, one of ordinary skill in the art would have a reasonable expectation of success because by substituting the NSAID acetylsalicylic acid (aspirin) for the NSAIDs detailed by Bouroubi (ibuprofen) and Radkova (flurbiprofen) both delivered in the form of a lozenge to treat a sore throat. The applicant is substituting a known equivalent acetylsalicylic acid for the NSAIDs identified by Bouroubi and Radkova used for the same purpose of treating a sore throat with a lozenge as taught by both Bouroubi and Radkova. Therefore, the invention of the instant claims was prima facie obvious at the time it was filed.
Claims 1, 8-10, 12, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Kutta et.al., Distribution of mucins and antimicrobial substances lysozyme and lactoferrin in the laryngeal subglottic region, J. Anat. (2008) 213, pp473–481 in view of Radkova, et.al., Efficacy of flurbiprofen 8.75 mg delivered as a spray or lozenge in patients with sore throat due to upper respiratory tract infection: a randomized, non-inferiority trial in the Russian Federation, Journal of Pain Research 2017:10 1591–1600 and in further view of Rathod, et.al., Medicated Lozenges as an Easy to Use Dosage Form, World Journal of Pharmaceutical Research, Volume 7, Issue 16, 2018, 305-322.
Response to Applicants’ Arguments
Applicant argues that the introduction of the Kutta et al. (J Anat. 213 (2008): 473-481 ("Kutta")) reference is not relevant because they do not disclose the use of lysozyme and lactoferrin, for the claimed NSAID selection.
The applicants’ argument is compelling, Kutta while defining the naturally occurring proteins lysozyme and lactoferrin and their function as a protective agent against microbial infection in the mucus membranes, did not indicate the use as part of a NSAID selection. Although the proteins lysozyme and lactoferrin are not in fact NSAIDs, the inclusion of the proteins is not suggested by Kutta.
The rejection is withdrawn.
Allowable Subject Matter
Claims 8-10, 12, 13 and 17 are objected to as being dependent on a rejected claim but would be allowable if rewritten in independent form including all of the limitations of the generic claim and any intervening claims.
Conclusion
Claims 1-4, 13 and 15 are rejected.
Claims 8-12 and 17 are allowable.
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.
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/P.R.G./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
