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 of claim 1, previous 103 rejections over Bykov et al (RU 2 149 632 C1) in view of Chu et al (“Effect of Particle Size on the Dissolution Behaviors of Poorly Water-soluble Drugs”, Archives of Pharmacal Research, vol.35 (7) (2012), pg.1187-1195) are hereby withdrawn (the amended claim 1 now requires a combination of a filler, a binder, a disintegrant, a lubricant, a glidant and a film coating agent, where each of the components are required to be chosen from the compounds listed in claim 1 and required to be present in the claimed amounts. Bykov in view of Chu does not teach or suggest the newly added limitations of instant claim 1). Therefore, applicant’s argument with respect to the withdrawn rejections are now moot.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Claim Objections
Claim 5 is objected to because of the following informalities: applicant need to change “the coating agent” to --- the film coating agent --- on lines 2-3 and on line 4. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 4 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
In claim 4, applicant recite that “the filler and the binder are present in a total amount of 30 to 300 parts by weight per 100 parts by weight of the active pharmaceutical ingredient.” However, claim 1 (from which claim 4 depends) states that the filler is present in the amount of 30 to 300 parts by weight per 100 parts by weight of the active pharmaceutical ingredient and that the binder is present in the amount of 0 to 100 parts by weight, and not 0, per 100 parts by weight of the active pharmaceutical ingredient. Since the filler has to be present in the amount of 30 parts by weight at the minimum and since the amount of the binder cannot be 0, the sum of the filler and the binder cannot be 30. Thus, claim 4 fails to further limit the subject matter of claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 6 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
(i) Claim 6 recites that “the active pharmaceutical ingredient is present in an amount of 56 to 61 parts by weight per 100 parts by weight of the pharmaceutical composition;”. However, claim 1, from which claim 6 depends, states that the active pharmaceutical ingredient is present in an amount of 20 to 60 parts by weight per 100 parts by weight of the pharmaceutical composition. Thus, claim 6 fails to further limit the subject matter of claim 1.
(ii) The amended claim 1 now requires a combination of the filler, binder, disintegrant, lubricant, glidant and a film coating agent. However, claim 6, which depends from claim 1 does not seem to require the presence of the lubricant or glidant of instant claim 1 (it is not clear whether the adjuvant I (sodium stearyl fumarate and/or sodium dodecyl sulfate) of claim 6 is representing the lubricant and/or glidant of instant claim 1 – see Paragraph 9 below).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 6 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 6 recites that “the carrier comprises adjuvant I, the adjuvant I is sodium stearyl fumarate and/or sodium dodecyl sulfate; the adjuvant I is present in an amount of 2.5 to 4 parts by weight per 100 parts by weight of the active pharmaceutical ingredient;”.
By such limitation, do applicant mean that the carrier of claim 1 additionally (or separately) comprises adjuvant I (sodium stearyl fumarate and/or sodium dodecyl sulfate), i.e., in addition to the components of claim 1 (including the lubricant and glidant of claim 1)? Or, is the term “adjuvant I” (sodium stearyl fumarate and/or sodium dodecyl sulfate) representing (or referring to) the lubricant and/or glidant of claim 1?
Appropriate correction and/or clarification is necessary.
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) 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over PAN (US 2016/0031819 A1) in view of Eivaskhani et al (US 2006/0018962 A1), Rigassi-Dietrich et al (US 2007/0197655 A1), Bykov et al (RU 2 149 632 C1 and its English translation), and (Chu et al (“Effect of Particle Size on the Dissolution Behaviors of Poorly Water-soluble Drugs”, Archives of Pharmacal Research, vol.35(7) (2012), pg.1187-1195) or Han et al (KR 10-2010-0053424 and its English translation).
Pan teaches (claim 19) a pharmaceutical composition comprising a therapeutically effective amount of the base addition salt of nitroxoline and one or more pharmaceutically acceptable carriers. Pan further teaches ([0089] and [0153]-[0154]) that its pharmaceutical composition can be formulated as tablets for oral administration.
As to the carriers, Pan teaches ([0091]) that its pharmaceutical composition comprise a pharmaceutically acceptable carriers, such as those widely-employed in the art of drug manufacturing, and they can include one or more of fillers, binding agents (such as hydroxypropyl methylcellulose – instant binder of claim 1), disintegrants, lubricants (such as stearyl fumarate) and glidants (such as colloidal silicon dioxide – instant glidant of claim 1 which is silica).
Pan does not teach instant film coating agent. However, as evidenced by Eivaskhani ([0033]), it is well known in the art to film-coat tablets in order to make the tablets easier to swallow, easier to distinguish from other tablets and to provide improved stability (shelf-life). Eivaskhani also teaches that particularly attractive coating product are based on film-forming polymers, such as HPMC (instant hydroxypropylmethyl cellulose) or PVA (instant polyvinyl alcohol). It would have been obvious to one skilled in the art to film-coat Pan’s nitroxoline tablet using HPMC or PVA (both of which are instant film coating agent of clam 1) with a reasonable expectation of making the tablet easier to swallow, easier to distinguish from other tablets and to provide improved stability. Thus, Pan in view of Eivaskhani teaches instant film coating agents of claim 1 (HPMC or PVA).
Pan does not teach what compounds can be used as its fillers or disintegrants. As evidenced by Rigassi-Dietrich ([0022]-[0023]), it is well known in the art that tableting aids commonly used in tablet formulation include fillers, binders, disintegrants, lubricants, glidants and film-formers, and as further evidenced by Rigassi-Dietrich ([0029] and [0031]), microcrystalline cellulose and crospovidone are known in the art as a preferably used filler and disintegrant, respectively. It would be obvious to one skilled in the art to use microcrystalline cellulose (instant filler of claim 1) as Pan’s filler and use crospovidone (instant disintegrant of claim 1) as its disintegrant with a reasonable expectation of success.
Although Pan teaches stearyl fumarate as an example for its lubricant, it does not explicitly teach instant sodium stearyl fumarate or magnesium stearate. However, as evidenced by Rigassi-Dietrich ([0034]), sodium stearyl fumarate and magnesium stearate (both of which are instant lubricants of claim 1) are well known in the art as preferably used lubricants. It would be obvious to one skilled in the art to use sodium stearyl fumarate or magnesium stearate as Pan’s lubricant with a reasonable expectation of success.
Thus, Pan in view of Eivaskhani and Rigassi-Dietrich teaches instant carrier comprising instant filler (microcrystalline cellulose), instant binder (hydroxypropyl methylcellulose), instant disintegrant (crospovidone), instant lubricant (sodium stearyl fumarate or magnesium stearate), instant glidant (silica) and instant film coating agent (hydroxypropyl methylcellulose (HPMC) or polyvinyl alcohol (PVA)).
As to the amounts of these carriers, Rigassi-Dietrich teaches (see [0042]) that the amounts of each type of additive employed, such as filler, binder, disintegrant, lubricant, glidant or film coat may vary within ranges conventional in the art: a filler may be present in a range of 0-80 wt.%; a binder may be present in a range of 0-20 wt.%; a disintegrant may be present in a range of 0-20 wt.%; a lubricant may be present in a range of 0.2-5 wt.%; a glidant may be present in a range of 0-5 wt.%; and a film coat may be present in the amount that ranges from 0 to 20 mg/cm2.
As to the amount of nitroxoline, Pan does not explicitly teach the weight percentage of its base addition salt of nitroxoline. However, Bykov et al (a reference which teaches a sugar-coated nitroxoline tablet) teaches ([0006-[0007]) that nitroxoline can be present (in the core of the tablet, i.e., in uncoated tablet) in the amount of 40.9 – 59.1 wt.% based on the total weight of the core composition (i.e., based on the total weight of the uncoated tablet).
As calculated by the Examiner (i.e., converted based on 100 pbw of the nitroxoline), this gives: 0-196 pbw of the filler; 0–49 pbw of the binder; 0-49 pbw of the disintegrant; 0.34-12 pbw of the lubricant; and 0-12 pbw of the glidant. All of these ranges overlap with instant ranges for the filler (30-300 pbw), binder (0-100 pbw), disintegrant (0-100 pbw), lubricant (0.25-20 pbw) and glidant (0-20 pbw), thus rendering instant ranges 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).
As to instant range for the film coating (3-15% by mass relative to the mass of the uncoated pharmaceutical composition), as discussed above, Rigassi-Dietrich generally teaches that a film coat may be present in the amount that ranges from 0 to 20 mg/cm2. Specifically, in its Example 2, Rigassi-Dietrich gives 3 embodiments of film-coated tablets. In the first embodiment, the weight percentage for the film coating relative to the mass of the uncoated tablet would be calculated as follows: 180 mg (total film-coated tablet weight) minus 170 mg (total tablet weight without the coating – i.e., uncoated tablet weight) would give 10 mg for the coating (only), which is then divided by 170 mg (uncoated tablet weight), which would give 5.88 mass% for the film coating relative to the mass of the uncoated tablet. Similarly, the weight percentages for the film coating relative to the mass of the uncoated tablet for the second embodiment and the third embodiment are calculated be 5 mass% and 3.8 mass%, respectively. Thus, Rigassi-Dietrich teaches that the film coating (relative to the mass of the uncoated tablet) can be present in an amount that ranges from 3.8 to 5.88 mass%. Such range fall within instant range (3-15% by mass) and thus teaches instant range.
As to instant range (20-60 pbw per 100 pbw of the pharmaceutical composition) for the amount of the active pharmaceutical ingredient (nitroxoline or its salt), as discussed above, Bykov et al teaches ([0006-[0007]) that nitroxoline can be present (in the core of the tablet) in the amount of 40.9 – 59.1 wt.% based on the total weight of the core composition (uncoated tablet). That is, this amount is for the nitroxoline in the uncoated tablet. The amount of the nitroxoline in the coated tablet (instant pharmaceutical composition) would be calculated as follows: (the range 40.9 - 59.1) divided by (100 + 3.8) (3.8 being the mass % for the coating) or divided by (100 + 5.88) (5.88 being the mass% for the coating) to give a range of 38.6 – 56.9 wt.% based on the coated tablet, which is the same as 38.6 – 56.9 pbw per 100 pbw of the coated tablet (instant pharmaceutical composition). Such range falls within instant range 20-60 pbw per 100 pbw of the pharmaceutical composition and thus teaches instant range.
Pan does not explicitly teach instant particle size D90 (10-100 mm) for its nitroxoline salt. However, as evidenced by Chu et al (see abstract) or Han et al (see 8th paragraph under chemical <Formula 1>), it is well known in the art that dissolution rate of poorly soluble drug (such as nitroxoline) is strongly related to the particle size distribution, and it is generally known in the art that reducing the particle size of the drug component increases the dissolution rate of the drug component. Han also states that as the particle size of the drug component decreases, the surface area increases, thereby increasing the chance of reacting with other additives included in the drug composition, thereby reducing the stability of the drug composition). Under the guidelines given by Chu or Han, instant range (10 to 100 mm) for the particle size D90 of the active pharmaceutical ingredient (nitroxoline) 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 discovering an optimum value (of D90) of a result effective variable involves only routine skill in the art. In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980).
Thus, Pan in view of Eivaskhani, Rigassi-Dietrich, Bykov and (Chu or Han) renders obvious instant claim 1.
With respect to instant claim 2, as discussed above, in instant case, the amount of nitroxoline was calculated to 38.6 – 56.9 pbw per 100 pbw of the coated tablet (instant pharmaceutical composition). This range falls within instant range 25-60 pbw per 100 pbw of the pharmaceutical composition and thus teaches instant range. Thus, Pan in view of Eivaskhani, Rigassi-Dietrich, Bykov and (Chu or Han) renders obvious instant claim 2.
With respect to instant claim 3, as already discussed above, Pan teaches the use of hydroxypropyl methylcellulose as its binding agent (instant binder of claim 3), and as calculated above by the Examiner, the amount of the binder is 0-49 pbw based on 100 pbw of the active pharmaceutical ingredient (nitroxoline). The range 0-49 pbw overlaps with instant range 2-50 pbw, thus rendering instant range prima facie obvious. In re Wertheim, supra. Thus, Pan in view of Eivaskhani, Rigassi-Dietrich, Bykov and (Chu or Han) renders obvious instant claim 3.
With respect to instant claim 4, as calculated above by the Examiner, the amount of the filler is 0-196 pbw based on 100 pbw of the active pharmaceutical ingredient, and the amount of the binder is 0–49 pbw based on 100 pbw of the active pharmaceutical ingredient. Thus, the amount for the sum of the filler and binder would be 0-245 pbw based on 100 pbw of the active pharmaceutical ingredient. The range 0-245 pbw overlaps with instant range 30-300 pbw based on 100 pbw of the active pharmaceutical ingredient, thus rendering instant range prima facie obvious. In re Wertheim, supra. Thus, Pan in view of Eivaskhani, Rigassi-Dietrich, Bykov and (Chu or Han) renders obvious instant claim 4.
With respect to instant claim 5, the Examiner established above that it would have been obvious to one skilled in the art to film-coat Pan’s nitroxoline tablet using HPMC (hydroxypropyl methylcellulose) (instant film coating agent of clam 5) with a reasonable expectation of making the tablet easier to swallow, easier to distinguish from other tablets and to provide improved stability, as taught by Eivaskhani. Furthermore, as calculated above by the Examiner, such film coating agent can be present in an amount that ranges from 3.8 to 5.88 mass% relative to the mass of the uncoated tablet. Although such range (a preferred range taught in Rigassi-Dietrich’s Example 2) does not overlap with instant range (9-13% by mass relative to the mass of the uncoated pharmaceutical composition), as already discussed above, Rigassi-Dietrich gives a general teaching that a film coat may be present in the amount that ranges from 0 to 20 mg/cm2. Under such general guideline given by Rigassi-Dietrich, instant range 9-13% by mass relative to the mass of the uncoated pharmaceutical composition would have been obvious to one having ordinary skill 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, Pan in view of Eivaskhani, Rigassi-Dietrich, Bykov and (Chu or Han) renders obvious instant claim 5.
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.
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/SIN J LEE/
Primary Examiner, Art Unit 1613
December 12, 2025
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