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 .
In view of the amendment, previous 112(b) rejection on claim 4 is hereby withdrawn.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1, 2, 4, 5 and 10-15 are rejected under 35 U.S.C. 103 as being unpatentable over Al-Ghazawi et al (US 2003/0211150 A1) in view of KARPUKHIN et al (WO 2021/037874 A1).
Al-Ghazawi teaches ([0001] and [0008]) an immediate release, Naproxen Sodium tablet comprising Naproxen Sodium and spray-dried mannitol, wherein the tablet has an improved dissolution rate of Naproxen Sodium. Specifically, in Example 3 (Formulation C), Al-Ghazawi teaches a tablet containing Naproxen Sodium, spray-dried mannitol, Mg-stearate (instant lubricant) and Cab-O-Sil (instant colloidal silicon dioxide). Al-Ghazawi’s Formulation C does not contain a super-disintegrant. However, Al-Ghazawi teaches ([0019] and [0021]) that a disintegrant such as sodium starch glycolate (instant super-disintegrant) may be present in its tablet. Thus, it would be obvious to one skilled in the art to add sodium starch glycolate into Al-Ghazawi’s Formulation C with a reasonable expectation of success.
Al-Ghazawi does not teach instant limitation “granules”. Karpukhin teaches (pg.4, lines 17-22) that while direct compression is the shortest, most effective and least complex way to produce tablets, some powders are difficult to compress. Granules of the same powder are often more easily compressed. Karpukhin also teaches (pg.2, lines 24-26) that compressing naproxen into a tablet is very difficult or impossible and that naproxen should be granulated before compressing. Karpukhin further teaches (pg.4, lines 23-24) that the process of forming granules involves agglomeration of fine particles into larger granules. Karpukhin teaches (pg.5, lines 5-8) that a particular compound (e.g., naproxen sodium) may be blended with other ingredients prior to granulation so that these ingredients are incorporated into the granules. Based on Karpukhin’s teaching, it would have been obvious to one skilled in the art to first form Al-Ghazawi’s powder ingredients (naproxen sodium, mannitol, Mg-stearate, Cab-O-Sil and sodium starch glycolate) into granules in order to make the tableting process easier. Al-Ghazawi’s mannitol, Mg-stearate (instant lubricant), Cab-O-Sil (instant colloidal silicon dioxide) and sodium starch glycolate (instant super-disintegrant) teach instant intragranular excipients of claim 1.
Al-Ghazawi does not teach instant limitation “wherein the tablet comprises 60-80% w/w naproxen sodium”. However, Karpukhin teaches (see Table 4 in Example 1, Tables 6 and 7 in Example 2, Table 13a and 13b in Example 6, and Table 14 in Example 8) that there can be from 39 wt.% to 73.7 wt.% (as calculated by the Examiner) of naproxen sodium in a tablet formed from naproxen sodium granules. Such range overlaps with instant range (60-80 wt.%) for the amount of naproxen sodium in the tablet, thus rendering instant rage prima facie obvious. In the case “where the [claimed] ranges overlap or lie inside ranges disclosed by the prior art,” a prima facie case of obviousness would exist which may be overcome by a showing of unexpected results, In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).
With respect to instant dissolution profile limitation, in Example 4, Al-Ghazawi performs a dissolution test according to USP-24 apparatus-2 (Paddles) using phosphate buffer pH 7.4 at 37oC at a rotation speed of 50 rpm to determine a dissolution rate for Formulation C (which is discussed above). The dissolution at 10 minutes is 78.4 (±4.6)%, and at 20 minutes, it is 96.5 (±0.7)%. The dissolution of 78.4 (±4.6)% at 10 minutes overlaps with instant range of at least 80%, and the dissolution of 96.5 (±0.7)% at 20 minutes does not overlap with instant dissolution value of 100%. However, the higher end (i.e., 97.2%) of Al-Ghazawi’s dissolution value is so close to the instant value of 100% that it is the Examiner’s position that Al-Ghazawi’s dissolution value of 96.5 (±0.7)% at 20 minutes would render instant dissolution value of 100% prima facie obvious. Where the claimed ranges and prior art do not overlap but are close enough that one skilled in the art would have expected them to have the same properties, a prima facie case of obviousness would also exist which may also be overcome by a showing of unexpected results, In re Titanium Metals Corporation of America v. Banner, 227 USPQ 773 (Fed. Cir. 1985). It is also to be noted that the dissolution of 96.5 (±0.7)% at 20 minutes obtained in Al-Ghazawi is a dissolution rate of Al-Ghazawi’s naproxen sodium tablet that has not been modified by the teaching of Karpukhin. Since Al-Ghazawi in view of Karpukhin teaches instant naproxen sodium tablet comprising granules comprising all of instant components, Al-Ghazawi’s naproxen sodium tablet as modified by the teachings of Karpukhin would naturally satisfy instant dissolution profile limitation (besides, even though applicant claim “100%” dissolution at 20 minutes, instant Fig.2 and Table 5 of present specification shows that the dissolution at 20 minutes is clearly below 100%).
Thus, Al-Ghazawi in view of Karpukhin renders obvious instant claim 1.
With respect to instant claims 2 and 5, Al-Ghazawi teaches ([0018]) that its Naproxen Sodium tablet may also contain lubricants such as stearic acid to improve processing of mixture of Naproxen Sodium used for the manufacture of the tablet. It would be obvious to one skilled in the art to further incorporate stearic acid into the granules containing Naproxen Sodium, mannitol, Mg-stearate, Cab-O-Sil and sodium starch glycolate (as discussed above) with a reasonable expectation of improving processing of mixture of Naproxen Sodium. Thus, Al-Ghazawi in view of Karpukhin renders obvious instant claims 2 and 5.
With respect to instant claim 4, Al-Ghazawi teaches ([0015]) that the spray-dried mannitol is present in its tablet in the amount of 10-90 wt.%. Such range overlaps with instant range of 10-20 wt.%, thus rendering instant range prima facie obvious. In re Wertheim, supra. Thus, Al-Ghazawi in view of Karpukhin renders obvious instant claim 4.
With respect to instant claims 10-12, since Al-Ghazawi’s Naproxen Sodium tablet as modified by Karpukhin’s teaching is an immediate release fast dissolution tablet like that of applicant, and since Al-Ghazawi’s formulation contains all of instant ingredients of claims 1 and 2, it is the Examiner’s position that such Naproxen Sodium tablet would naturally satisfy instant disintegration time limitation of claim 10, instant hardness limitation of claim 11 and instant friability limitation of claim 12. Thus, Al-Ghazawi in view of Karpukhin renders obvious instant claims 10-12.
With respect to instant claims 13-15, Al-Ghazawi teaches ([0002]) that Naproxen Sodium is a well-known anti-inflammatory, analgesic and antipyretic (drug used to reduce fever) agent used in the symptomatic treatment of acute and chronic rheumatoid arthritis, osteoarthritis, primary dysmenorrhea (painful menstrual cramps) and for relief of mild to moderate pain. Thus, it would be obvious to one skilled in the art to use Al-Ghazawi’s Naproxen Sodium tablet (as modified by Karpukhin’s teaching) to treat aches and pains caused by arthritis or menstrual cramps or to reduce fevers in a subject with a reasonable expectation of success. Thus, Al-Ghazawi in view of Karpukhin renders obvious instant claims 13-15.
Claim(s) 6-9 are rejected under 35 U.S.C. 103 as being unpatentable over Al-Ghazawi et al (US 2003/0211150 A1) in view of KARPUKHIN et al (WO 2021/037874 A1) as applied to claim 1 above, and further in view of Yang et al (US 2019/0054024 A1).
With respect to instant claim 6, Al-Ghazawi in view of Karpukhin does not teach instant range for the amount of the granules in the naproxen sodium tablet. Yang teaches ([0001], [0008], [0012]) that its solid dosage forms may exhibit an immediate or modified release of the drug upon administration to a patient and states ([0056]) that “immediate release” refers to a dosage form that releases about 100% of the drugs preferably in 45 minutes or less and most preferably in 30 minutes or less following administration to a subject. Yang further teaches ([0015]) that depending on the amount and type of extragranular excipients, the release rate of the drug from the final dosage form can be adjusted to a desired profile. Yang then lists (in [0121]-[0133]) types and amounts of the extragranular excipients that can be used to adjust the release rate of the drug to a desired profile. Since Al-Ghazawi’s naproxen sodium tablet is for immediate release, under the general guidelines given by Yang, determining the types and optimum amounts for the extragranular excipients that would achieve the immediate release for Al-Ghazawi’s naproxen sodium tablet (modified by Karpukhin) would be within a realm of one of ordinary skill in the art, and the amounts for the extragranular excipients thus determined would in turn give the amounts for the granules. Thus, instant range (at least 85 wt.%) for the amount of granules based on the total weight of the naproxen sodium tablet would have been obvious to one skilled in the art before the effective filing date of the claimed invention since it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 105 USPQ 233. Thus, Al-Ghazawi in view of Karpukhin and Yang renders obvious instant claim 6.
With respect to instant claims 7 and 8, Al-Ghazawi in view of Karpukhin does not teach instant limitations. However, as discussed above, Yang teaches that depending on the amounts and types of extra-granular excipients, the release rate of the drug from the final dosage form can be adjusted to a desired profile, and Yang lists (in [0121]-[0133]) types and amounts of the extragranular excipients that can be used to adjust the release rate of the drug to a desired profile Since Al-Ghazawi’s naproxen sodium tablet is for immediate release, under the general guidelines given by Yang, determining the types (and amounts) of extragranular excipients that would achieve the immediate release for Al-Ghazawi’s naproxen sodium tablet (modified by Karpukhin) would be within a realm of one of ordinary skill in the art, and thus instant combinations of extragranular excipients of claims 7 and 8 would have been obvious. Thus, Al-Ghazawi in view of Karpukhin and further in view of Yang renders obvious instant claims 7 and 8.
With respect to instant claim 9, AL-Ghazawi does not teach instant film coating. Yang teaches ([0133]) that tablets may be coated with a tablet coating for aesthetic purposes and gives as an example, OPADRY, a coating that comes in a variety of colors as well as clear. It would be obvious to one skilled in the art to provide a film coating for Al-Ghazawi’s Naproxen Sodium tablet (as modified by the teachings of Karpukhin) to provide an aesthetic feature. Thus, Al-Ghazawi in view of Karpukhin, and further in view of Yang renders obvious instant claim 9.
Response to Arguments
With respect to instant claims 1 and 2, applicant argue that Al-Ghazawi teaches ([0004] and [0007]) against granulation because it is costly. However, the prior art mentioned in [0004] of Al-Ghazawi involves wet grinding of naproxen to form nano-particles, which is a very costly step, and Al-Ghazawi is not teaching against granulation in general. Besides, Karpukhin provides a strong motivation to first form Al-Ghazawi’s powder ingredients into granules by teaching that compressing naproxen into a tablet directly is very difficult or impossible and thus naproxen should be granulated before compressing.
Applicant also argue that Al-Ghazawi provides empirical evidence that teaches against granulation. Applicant then point to the results in Table 1, which indicate that at 10 minutes, Formulation B (spray-dried) shows 96.0% dissolution whereas Formulation D (granular) shows 60.5% dissolution. Applicant state, “Al-Ghazawi explicitly concludes that a tablet with spray-dried mannitol (for direct compression) has a faster dissolution rate than a tablet with granular mannitol (see Al-Ghazawi at [0050] and Table 1).” Applicant thus argue that this is a clear teaching away from using granulated components, as it shows that granulation is severely detrimental to achieving the fast dissolution that is a key objective of Al-Ghazawi. The Examiner disagrees. The only thing shown by the comparison between Formulation B and D is that when spray dried mannitol was used in the tablet composition, a faster dissolution rate was obtained than when granular mannitol was used. There is no general teaching in Al-Ghazawi that granulating all of the ingredients (including the naproxen sodium) prior to tableting is detrimental to achieve the fast dissolution.
Applicant furthermore argue that the cited prior art teaches away from the claimed high drug load of 60-80 wt.% of naproxen sodium because Al-Ghazawi’s data in Table 1 shows that Formulation B, with a lower drug load of 24.4 wt.% naproxen sodium, achieved faster dissolution (96.0% at 10 min) than Formulations A and C, with a higher drug load of 31.4 wt.% and slower dissolution (92.9% and 78.4%, respectively). Applicant thus argue that this would lead a POSA to believe that decreasing the drug load is the path to faster dissolution. Applicant argue that present invention achieves an unexpectedly rapid and complete dissolution profile at a high drug load, which runs contrary to the teachings of the prior art. However, applicant’s such argument is found to be unpersuasive because applicant’s comparison of Al-Ghazawi’s Formulation B against Al-Ghazawi’s Formulations A and C is not fair since the ingredients contained in each of the formulations are different. That is, in order to show the effect of naproxen sodium amount (wt.%) on the dissolution rate, one has to keep all the other ingredients of Formulations A, B and C the same, both in kind and amount, so as to make a fair comparison.
Finally, applicant argue that the prior art does not teach the claimed dissolution profile wherein 100% naproxen sodium being dissolved at 20 minutes because Al-Ghazawi’s results of 96.5% at 20 minutes does not make the claimed 100% obvious. Applicant argue that achieving complete (100%) dissolution in the pharmaceutical arts is a discrete and significant technical achievement and that claimed profile represents a specific, advantageous performance benchmark that the prior art fails to meet or suggest. However, as already mentioned in Paragraph 4 above, even though applicant claim “100%” dissolution at 20 minutes, instant Fig.2 and Table 5 of present specification shows that the dissolution at 20 minutes is clearly below 100%. Besides, the dissolution of 96.5 (±0.7)% at 20 minutes obtained in Al-Ghazawi is a dissolution rate of Al-Ghazawi’s naproxen sodium tablet that has not been modified by the teaching of Karpukhin. As already discussed above, since Al-Ghazawi in view of Karpukhin teaches instant naproxen sodium tablet comprising granules comprising all of instant components, it is the Examiner’s position that Al-Ghazawi’s naproxen sodium tablet as modified by the teachings of Karpukhin would naturally satisfy instant dissolution profile limitation.
With respect to instant claims 6-9, applicant argue that the combination with Yang is improper because the specific teachings relied upon by the Examiner are taken from the extended release, abuse-deterrent context of Yang, which is fundamentally different from the immediate release goals of the present invention. Applicant argue that the entirety of Yang’s substantive teachings, including all working examples and data tables, are exclusively directed to extended release dosage forms and that a POSA would find no guidance in Yang for formulating a tablet that dissolves completely in under 20 minutes. Applicant argue that in Yang’s ER system, excipients are chosen to retard and control dissolution over many hours whereas in present invention, they are chosen to accelerate disintegration and dissolution. Applicant argue that a POSA would not be motivated to apply formulation strategies from an ER system to an IR system as it would be expected to frustrate the goal of rapid release. The Examiner disagrees. Yang clearly teaches ([0001], [0008], [0012]) that its solid dosage forms may exhibit an immediate or modified release of the drug upon administration to a patient and states ([0056]) that “immediate release” refers to a dosage form that releases about 100% of the drugs preferably in 45 minutes or less and most preferably in 30 minutes or less following administration to a subject. Yang further teaches ([0015]) that depending on the amount and type of extragranular excipients, the release rate of the drug from the final dosage form can be adjusted to a desired profile. For example, the addition of a water soluble filler such as mannitol to the drug-loaded particles can increase the release rate of the drug from a tablet. Yang then lists (in [0121]-[0133]) types and amounts of the extragranular excipients that can be used to adjust the release rate of the drug to a desired profile. Since Al-Ghazawi’s naproxen sodium tablet is for immediate release, under the guidelines given by Yang, determining the types and optimum amounts for the extragranular excipients that would achieve the immediate release for Al-Ghazawi’s naproxen sodium tablet (modified by Karpukhin) would be within a realm of one of ordinary skill in the art. Thus, the Examiner does not agree with applicant’s argument that a POSA would find no guidance in Yang for formulating a tablet that dissolves completely in under 20 minutes.
For the reasons stated above, instant 103 rejections over Al-Ghazawi in view of Karpukhin still stand.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SIN J. LEE whose telephone number is (571)272-1333. The examiner can normally be reached on M-F 9 am-5:30pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian Kwon can be reached on 571-272-0581. 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 http://pair-direct.uspto.gov . Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
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 .
/SIN J LEE/
Primary Examiner, Art Unit 1613
March 7, 2026