DETAILED ACTION
Claims 1-30 are pending and under consideration on the merits.
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 .
Status of the Rejections
The 112(b) rejections are withdrawn in view of the amendment.
The 103 rejections are revised in view of the amendment.
The double patenting rejection is withdrawn in view of the filing and approval of a terminal disclaimer.
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 nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2 and 6-30 are rejected under 35 U.S.C. 103 as unpatentable over Chrzan et al. (US Pat. Pub. 2008/0299211) in view of Amith et al. (US Pat. Pub. 2016/0184284; of record in IDS).
As to claims 1-2 and 6-30, Chrzan discloses an aqueous pharmaceutical suspension having a pH of about 4.25 to about 9.43 (encompassing the range of claim 1), 0.03-4.80 wt% fexofenadine zwitterionic dihydrate Form 1, 0.01 to 0.20 wt% wetting agent, 0.10 to 0.50 wt% hydrocolloid gum, a sweetener system comprising 5-40 wt% sucrose and 0-40 wt% xylitol wherein the ratio of sucrose to xylitol is equal to or greater than 1:1, a preservative system comprising parabens, 0.06-0.26% edetate disodium, and 0.01 to 0.30% potassium sorbate, a buffer system comprising 0.06 to 1.05% sodium phosphate monobasic and 0.32% to 2.69% sodium phosphate dibasic hydrate, 0.1 to 15% propylene glycol, and 0.20% to 0.70% of a flavoring agent (see claims 1-2, 23, 44-52, 65-67, and 77-79 of Chrzan). The foregoing ranges match or overlap the ranges recited for these ingredients by claims 1-2, 6, 9-11, 15, 17-26, and 29. Addtionally, discovering optimum or working ranges involves only routine skill in the art in cases where the general conditions of a claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claims 6-8, Chrzan discloses that at least 0% of the fexofenadine compound has a particle size of less than about 40 microns, which reads on the ranges of these claims (claims 5-7 of Chrzan).
As to claim 16, the hydrocolloid gum may be xanthan gum (claim 14 of Chrzan).
Regarding claims 12-14, the wetting agent may be ionic such as Poloxamer 188 or Poloxamer 407 (claims 54-55 of Chrzan).
As to claims 27-28, the composition further comprises 0.05 to 0.10% of an opacifying agent such as titanium dioxide, which overlaps the range of claim 27 (claims 71-76 of Chrzan).
As to claim 29, Chrzan also teaches that the sodium phosphate dibasic hydrate may be a heptahydrate as recited by this claim (claim 52 of Chrzan).
Regarding claim 30, the flavoring agent may be artificial raspberry cream or orange cream (claims 80-82 of Chrzan).
As to claims 1-2 and 6-30, Chrzan does not further expressly disclose that the composition is free of parabens such that the preservative system consists only of edetate disodium and potassium sorbate as recited by claim 1.
Amith discloses liquid pharmaceutical compositions comprising fexofenadine (paragraph 1). Amith teaches that while prior art fexofenadine formulations comprise parabens as preservatives, parabens have been linked to negative health effects such as drug allergies and negative effects on spermatogenesis (paragraph 10). Amith teaches that its compositions are therefore preferably free of parabens, and that it was found that by keeping the extra water in the composition below a specified range, the paraben preservatives could be removed while still maintaining biological stability (paragraphs 64-69).
As to claims 1-2 and 6-30, it would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the present invention to modify the composition of Chrzan by removing all parabens. The skilled artisan would have been motivated to do so because Amith teaches that parabens have been linked to negative health effects such as drug allergies and negative effects on spermatogenesis, and the skilled artisan would have had a reasonable expectation of success in removing the parabens because Amith expressly discloses that preservatives, including parabens, can be removed from aqueous fexofenadine formulations while still maintaining biological stability by controlling the extra water content of the formulation, and additionally because Chrzan itself discloses non-paraben preservatives that can be used in its formulation including edetate sodium and potassium sorbate as discussed above. Thus, the prior art provides evidence of an explicit advantage that would result from modifying the Chrzan disclosure as discussed above. The strongest rationale for combining references is a recognition, as is the case here, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. In re Sernaker, 702 F.2d 989, 994-95, 217 USPQ 1, 5-6 (Fed. Cir. 1983). See also Dystar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick, 464 F.3d 1356, 1368, 80 USPQ2d 1641, 1651 (Fed. Cir. 2006) (“Indeed, we have repeatedly held that an implicit motivation to combine exists not only when a suggestion may be gleaned from the prior art as a whole, but when the ‘improvement’ is technology-independent and the combination of references results in a product or process that is more desirable, for example because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient. Because the desire to enhance commercial opportunities by improving a product or process is universal—and even common-sensical—we have held that there exists in these situations a motivation to combine prior art references even absent any hint of suggestion in the references themselves.”).
Claims 3-5 are rejected under 35 U.S.C. 103 as unpatentable over Chrzan et al. (US Pat. Pub. 2008/0299211) in view of Amith et al. (US Pat. Pub. 2016/0184284 as applied to claims 1-2 and 6-30 above, and further in view of Liversidge et al. (US Pat. Pub. 2006/0216353).
The teachings of Chrzan and Amith are relied upon as discussed above, but they do not further expressly disclose that the preservative system comprises domiphen bromide (claims 3 and 5) or cetylpyridinium chloride (claim 4).
Liversidge discloses suspensions comprising an antihistamine such as fexofenadine (paragraphs 23, 28, 81-82) along with one or more cationic stabilizers for the poorly soluble fexofenadine such as cetylpyridinium chloride or domiphen bromide (paragraph 19, 86, 103) and which are used in the amount of 0.001 to 99.5 wt% (paragraphs 117 and 119).
As to claims 3-5, it would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the present invention to modify the fexofenadine composition of Chrzan and Amith as combined supra by incorporating cetylpyridinium chloride and domiphen bromide in amounts within the recited ranges, because Liversidge teaches that these compounds are useful in such amounts as stabilizers for poorly soluble antihistamine compounds such as fexofenadine.
Response to Applicant’s Arguments
Applicant argues that Chrzan discloses formulations that require paraben and that further comprise sorbic acid or potassium sorbate or benzyl alcohol. Applicant concludes that these additional compounds are not sufficient when used alone in the Chrzan formulations but are used in combination with parabens. Applicant argues that it was known that parabens show synergism with EDTA and also with benzyl alcohol, and further argues that despite the potential downsides of parabens, the amounts of parabens required by Chrzan would be safe for human use based upon their NOEL value, and cites to a European Commission Opinion as supporting the use of up to 0.14% butylparaben as being safe. Amit is said to provide a different solution for stable fexofenadine compositions by lowering water content, allowing for compositions that are free or substantially free of parabens, which Amit defines as less than 3 wt%, and Applicant argues that the amount taught by Chrzan is already below 3 wt%. Applicant concludes that the skilled artisan would be disinclined to modify the Chrzan formulation by excluding parabens, due to the known synergism with other preservatives.
In response, while Applicant argues that Chrzan’s teachings of parabens in combination with additional preservatives implies that the additional preservatives would not be sufficient by themselves, the skilled artisan reading Amit would learn that non-paraben preservatives in fact can be sufficient so long as the water content is controlled, e.g., to below 30%, and it follows that the synergistic effects obtained by combining parabens with other preservatives therefore would not be needed if water content is so controlled. While Applicant asserts that the use of up to 0.14% butylparaben is believed to be safe, the skilled artisan still would have had a motivation to eliminate parabens in light of unfavorable public perception of these compounds, which could lead to problems with patient compliance with fexofenadine formulations.
Applicant also argues that the skilled artisan reading Chrzan and Amith would be motivated to use a low water content and simply eliminate preservatives entirely, and further argues that the skilled artisan would recognize that the claimed invention requires much larger amounts of water.
In response, and as acknowledged by Applicant, Amith itself suggests that its formulation may still comprise small amounts of preservatives even with control of water content, so the skilled artisan would not have thought it necessary to eliminate all preservatives from the Chrzan composition. Additionally, the Office does not agree that the claimed composition requires much larger amounts of water. Claim 1, for example, recites the use of up to 40 wt% each of sucrose and xylitol, which allows for the presence of less than 20 wt% water in light of the remaining required ingredients.
Applicant also argues that the claimed invention provides unexpected results by identifying that using potassium sorbate in fexofenadine formulations can result in bioequivalence to paraben containing formulations.
In response, Applicant’s finding is not viewed as unexpected over the prior art, since Amith teaches that fexofenadine formulations that are substantially or even entirely free of preservatives can be substantially equivalent in stability to the paraben-containing Allegra® pediatric fexofenadine suspension (see paragraphs 68-69).
Regarding claims 3 and 5, Applicant argues that Liversidge would not motivate the use of cetylpyridinium chloride or domiphen bromide in a fexofenadine composition as preservatives in place of the synergistic components of Chrzan’s preservative system, because it teaches that these compounds are in fact used as surface stabilizers for corticosteroids, and does not suggest using these compounds in a composition that comprises an antihisitamine alone and omits the corticosteroid.
In response, this is not persuasive because the claims do not exclude the presence of a corticosteroid, and the skilled artisan would have been motivated to not use the synergistic preservative system of Chrzan for the reasons discussed above, i.e., in order to omit undesirable paraben compounds from the formulation.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GAREN GOTFREDSON whose telephone number is (571)270-3468. The examiner can normally be reached on M-F 9AM-6PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, David Blanchard can be reached on 5712720827. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see https://ppair-my.uspto.gov/pair/PrivatePair. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/GAREN GOTFREDSON/Examiner, Art Unit 1619
/BENNETT M CELSA/ Primary Examiner, Art Unit 1600
Prosecution Insights