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112(d) rejection on claim 4, previous 112(d) rejection on claim 6 and previous 112(b) rejection on claim 6 are hereby withdrawn.
It is to be noted that upon reconsideration, a previously used secondary reference, Han et al (KR 10-2010-0053424), was replaced by Bojnanska et al (“Determination of Critical Parameters of Drug Substance Influencing Dissolution: A Case Study”, BioMed Research International, Volume 2014, Article ID 929248, 9 pages, obtained from the website: https://pmc.ncbi.nlm.nih.gov/articles/PMC4181942/ ) in this Office Action.
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.
Claims 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), 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) and Bojnanska et al (“Determination of Critical Parameters of Drug Substance Influencing Dissolution: A Case Study”, BioMed Research International, Volume 2014, Article ID 929248, 9 pages, obtained from the website: https://pmc.ncbi.nlm.nih.gov/articles/PMC4181942/ ).
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 Bojnanska et al (see pg.8, 1st paragraph, lines 3-5), 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. However, Bojnanska also states (see pg.7, last paragraph and pg.8, 1st paragraph) that although a particle size reduction and an increase of the surface area are recommended to increase the dissolution rate of drugs in general, for some drugs (especially for those that are lipophilic in nature), particle size reduction can result in aggregation of the material. This causes a consequent reduction in the effective surface area of the drugs exposed to liquids and hence a reduction in their dissolution rate. That is, the improvement of solubility by particle size reduction/increase of the surface area ceases when the particle size reaches a particular value and beyond the particular value, the solubility of the drugs decreases. Under the guidelines given by Chu and/or Bojnanska, 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, Chu and Bojnanska 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, Chu and Bojnanska 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, Chu and Bojnanska 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, Chu and Bojnanska 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, Chu and Bojnanska renders obvious instant claim 5.
Claim 6 is 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), 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) and Bojnanska et al (“Determination of Critical Parameters of Drug Substance Influencing Dissolution: A Case Study”, BioMed Research International, Volume 2014, Article ID 929248, 9 pages, obtained from the website: https://pmc.ncbi.nlm.nih.gov/articles/PMC4181942/ ) as applied to claim 1 above, and further in view of MAO et al (US 2011/0111024 A1) and Jacobsen et al (US 2015/0203499 A1).
With respect to instant limitations as to the particle size D90, D50 and D10 of the active pharmaceutical ingredient, Pan does not explicitly teach instant D90, D50 and D10 for its nitroxoline salt. However, as evidenced by Chu et al (see abstract) or Bojnanska et al (see pg.8, 1st paragraph, lines 3-5), 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. However, Bojnanska also states (see pg.7, last paragraph and pg.8, 1st paragraph) that although a particle size reduction and an increase of the surface area are recommended to increase the dissolution rate of drugs in general, for some drugs (especially for those that are lipophilic in nature), particle size reduction can result in aggregation of the material. This causes a consequent reduction in the effective surface area of the drugs exposed to liquids and hence a reduction in their dissolution rate. That is, the improvement of solubility by particle size reduction/increase of the surface area ceases when the particle size reaches a particular value and beyond the particular value, the solubility of the drugs decreases. Under the guidelines given by Chu and/or Bojnanska, instant D90 range (10 to 100 mm), instant D50 range (4-35 mm) and instant D10 range (0.1-6 mm) of the active pharmaceutical ingredient (nitroxoline salt) 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, supra.
With respect to instant limitation as to the active pharmaceutical ingredient being present in the amount of 56-61 pbw per 100 pbw of the pharmaceutical composition, as already discussed in Paragraph 5 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 overlaps with instant range 56-61 pbw per 100 pbw of the pharmaceutical composition, thus rendering instant range prima facie obvious. In re Wertheim, supra.
With instant limitations as to the filler being starch, lactose or microcrystalline cellulose, as to the binder being polyvinylpyrrolidone and/or starch and as to the amount of the filler and binder together being 56.5 – 70 pbw per 100 pbw of the active pharmaceutical ingredient, as already discussed in Paragraph 5 above, Pan in view of Eivaskhani, Rigassi-Dietrich, Bykov, Chu and Bojnanska renders obvious the use of 0-196 pbw of the filler (such as microcrystalline cellulose) based on 100 pbw of the nitroxoline and the use of 0–49 pbw of the binder (such as HPMC) based on 100 pbw of the nitroxoline. Furthermore, as evidenced by Mao et al (see [0069]) HPMC (used in Pan) and instant polyvinyl pyrrolidone are known in the art as equivalently or interchangeably used binding agents in tablet dosage forms. Thus, it would have been obvious to one skilled in the art to use 0-49 pbw of polyvinyl pyrrolidone (per 100 pbw of the nitroxoline) as Pan’s binding agent with a reasonable expectation of success, and the sum of the filler (0-196 pbw) and the binder (0-49 pbw) would be 0-245 pbw per 100 pbw of the nitroxoline. Such range overlaps with instant range 56.5-70 pbw (per 100 pbw of the active pharmaceutical ingredient) for the amount of the filler and binder together, thus rendering instant range prima facie obvious. In re Wertheim, supra.
With respect to instant limitation as to the disintegrant being low-substituted hydroxypropyl cellulose and being present in the amount of 5-6 pbw per 100 pbw of the active pharmaceutical ingredient, as discussed in Paragraph 5 above, Pan in view of Eivaskhani, Rigassi-Dietrich, Bykov, Chu and Bojnanska renders obvious the use of 0-49 pbw of disintegrants (such as crospovidone) based on 100 pbw of the nitroxoline. Furthermore, as evidenced by MAO et al ([0072]), it is known in the art that crospovidone and instant low-substituted hydroxypropyl cellulose are equivalently or interchangeably used as disintegrants in a table formulation. Thus, it would be obvious to one skilled in the art to use 0-49 pbw of low-substituted hydroxypropyl cellulose per 100 pbw of the nitroxoline as Pan’s disintegrant with a reasonable expectation of success. The range 0-49 pbw (per 100 pbw of the nitroxoline) for the amount of the disintegrant (low-substituted hydroxypropyl cellulose) overlaps with instant range 5-6 pbw(per 100 pbw of the active pharmaceutical ingredient) for the amount of the disintegrant, thus rendering instant range prima facie obvious. In re Wertheim, supra.
With respect to instant limitation as to the lubricant being sodium stearyl fumarate, as discussed in Paragraph 5 above, Pan in view of Eivaskhani, Rigassi-Dietrich, Bykov, Chu and Bojnanska renders obvious the use of 0.34-12 pbw of the lubricant (such as sodium stearyl fumarate).
With respect to instant limitation as to the glidant being sodium dodecyl sulfate and as to the amount of lubricant and glidant together being 2.5 – 4 pbw per 100 pbw of the active pharmaceutical ingredient, as discussed in Paragraph 5 above, Pan in view of Eivaskhani, Rigassi-Dietrich, Bykov, Chu and Bojnanska renders obvious the use of 0-12 pbw of the glidant (such as silica). Furthermore, as evidenced by Jacobsen et al ([0382]), it is known in the art that silica (silicon dioxide) and instant sodium dodecyl sulfate are equivalently or interchangeably used as glidants for use in a tablet. Thus, it would be obvious to one skilled in the art to use 0-12 pbw of sodium dodecyl sulfate as Pan’s glidant with a reasonable expectation of success. Also, as discussed above, Pan in view of Eivaskhani, Rigassi-Dietrich, Bykov, Chu and Bojnanska renders obvious the use of 0.34-12 pbw of the lubricant (such as sodium stearyl fumarate). Thus, the sum of the lubricant and the glidant in instant case would be 0.34-24 pbw per 100 pbw of the nitroxoline. Such range overlaps with instant range 2.5-4 pbw for the amount of lubricant and glidant together per 100 pbw of the active pharmaceutical ingredient, thus rendering instant range prima faice obvious. In re Wertheim, supra.
With respect to instant limitation as to the film coating agent being HPMC and being present in the amount of 9-13 mass% relative to the mass of the uncoated pharmaceutical composition, such limitation was already addressed above in Paragraph 5 while rejecting instant claim 5.
Thus, Pan in view of Eivaskhani, Rigassi-Dietrich, Bykov, Chu and Bojnanska, and further in view of Mao and Jacobsen renders obvious instant claim 6.
Double Patenting
The nonstatutory 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 nonstatutory 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 1-5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3 of copending Application No. 17/632,521 (reference application) (with 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), which is being cited here merely to support the Examiner’s assertion that 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).
Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reason:
Claim 1 of App.’521 teaches the following:
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Thus, the pharmaceutical composition of claim 1 of App.’521 comprises 30-65 wt.% nitroxoline (i.e., 30-65 pbw of nitroxoline per 100 pbw of the pharmaceutical composition), 25-65 wt.% of a filler which can be microcrystalline cellulose (i.e., 38-216 pbw of filler per 100 pbw of nitroxoline, as calculated by the Examiner), 1-5 wt.% of a disintegrating agent which can be cross-linked polyvinylpyrrolidone (crospovidone) (i.e., 1.5-16 pbw of disintegrating agent per 100 pbw of nitroxoline), 1-4 wt.% of a binder which can be hydroxypropyl methylcellulose or starch (i.e., 1.5-13.3 pbw of binder per 100 pbw of nitroxoline), and 0.5-4 wt.% of lubricant which is sodium dodecyl sulfate (i.e., 0.8-13.3 pbw of lubricant per 100 pbw of nitroxoline). Furthermore, the sodium dodecyl sulfate also teaches instant glidant. Thus, the composition of claim 1 of App.’521 also contains 0.5-4 wt.% of instant glidant which is sodium dodecyl sulfate (i.e., 0.8-13.3 pbw of glidant per 100 pbw of nitroxoline). Claim 3 of App.’521 further teaches that the pharmaceutical composition of claim 1 comprises a coating agent which can be polyvinyl alcohol, and the weight gain of the coating agent is 7-15 wt.% (i.e., 7-15 mass% relative to the mass of the uncoated pharmaceutical composition). Thus, claims 1 and 3 of App.’521 teach instant claim 1 except for instant limitation as to the particle size D90 of the active pharmaceutical ingredient (nitroxoline) being 10-100 mm. However, claim 1 of App.’521 teaches that the dissolution rate of the pharmaceutical composition at 60 min is ≥ 80%. Since the pharmaceutical composition of claims 1 and 3 of App.’521 contains all of instant ingredients in the amounts that fall within instant ranges and since claim 1 of App.’521 teaches that the pharmaceutical composition has a dissolution rate at 60 min is ≥ 80% (which meets instant moderate dissolution rate), it is the Examiner’s position that it follows that the particle size D90 of the nitroxoline would range from 10-100 mm as instantly claimed (and would also range from 10-70 mm as instantly claimed in claim 2) because as evidenced by Chu et al (see abstract), 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. Thus, claims 1 and 3 of App.’521 render obvious instant claims 1-3.
With respect to instant claim 4, as discussed above, the pharmaceutical composition as taught in claims 1 and 3 of App.’521 contains 38-216 pbw of filler per 100 pbw of nitroxoline and 1.5-13.3 pbw of binder per 100 pbw of nitroxoline. Thus, the sum of the filler and binder is 39.5 - 229.3 pbw per 100 pbw of nitroxoline. Thus, claims 1 and 3 of App.’521 render obvious instant claim 4.
With respect to instant claim 5, as discussed above, the pharmaceutical composition as taught in claims 1 and 3 of App.’521 contains a coating agent which can be polyvinyl alcohol in the amount of 7-15 mass% relative to the mass of the uncoated pharmaceutical composition. Claim 3 of App.’521 further teaches the equivalence of polyvinyl alcohol and gastric-soluble film coating premix containing HPMC. Thus, it would be obvious to one skilled in the art to use 7-15 mass% (relative to the mass of the uncoated pharmaceutical composition) of gastric soluble film coating premix containing HPMC with a reasonable expectation of success. The range 7-15 mass% overlaps with instant range 9-13 mass% for the amount of the film coating agent, HPMC (as claimed in instant claim 5), thus rendering instant range prima facie obvious. In re Wertheim, supra. Alternatively, instant range of claim 5 for the amount of the film coating agent, HPMC (relative to the mass of the uncoated pharmaceutical composition) 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, claims 1 and 3 of App.’521 render obvious instant claim 5.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 6 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3 of copending Application No. 17/632,521 in view of MAO et al (US 2011/0111024 A1).
Since the pharmaceutical composition of claims 1 and 3 of App.’521 contains all of instant ingredients in the amounts that fall within instant ranges and since claim 1 of App.’521 teaches that the pharmaceutical composition has a dissolution rate at 60 min is ≥ 80% (which meets instant moderate dissolution rate), it is the Examiner’s position the pharmaceutical composition of claims 1 and 3 of App.’521 would naturally satisfy instant limitations as to the D90 of the nitroxoline being 10-100 mm, D50 of the nitroxoline being 4-35 mm and D10 of the nitroxoline being 0.1-6 mm as recited in instant claim 6.
As discussed above, the pharmaceutical composition of claim 1 of App.’521 contains 30-65 pbw of nitroxoline per 100 pbw of the pharmaceutical composition. The range 30-65 pbw overlaps with instant range 56-61 pbw for the amount of instant active pharmaceutical ingredient, thus rendering instant range prima facie obvious. In re Wertheim, supra.
As discussed above, the pharmaceutical composition of claim 1 of App.’521 contains a filler (microcrystalline cellulose) and a binder (such as HPMC or starch), and the sum of the filler and binder is 39.5 - 229.3 pbw per 100 pbw of nitroxoline. The range 39.5-229.3 pbw overlaps with instant range 56.5 - 70 pbw for the amount of the filler and binder together, thus rendering instant range prima facie obvious. In re Wertheim, supra.
With respect to instant limitation as to the disintegrant being low-substituted hydroxypropyl cellulose and being present in the amount of 5-6 pbw per 100 pbw of the active pharmaceutical ingredient, as already discussed above, the pharmaceutical composition of claim 1 of App.’521 contains 1.5-16 pbw of disintegrating agent (crospovidone) per 100 pbw of nitroxoline. The range 1.5-16 pbw overlaps with instant range 5-6 pbw for the amount of disintegrant, thus rendering instant range prima facie obvious. In re Wertheim, supra. Furthermore, as evidenced by MAO et al ([0072]) it is known in the art that crospovidone and instant low-substituted hydroxypropyl cellulose are equivalently or interchangeably used as disintegrants in a table formulation. Thus, it would be obvious to one skilled in the art to use low-substituted hydroxypropyl cellulose as the disintegrant in the pharmaceutical composition of claim 1 of App.’521 with a reasonable expectation of success.
With respect to instant limitation as to the lubricant being sodium stearyl fumarate, as already discussed above, the pharmaceutical composition of claim 1 of App.’521 contains 0.8-13.3 pbw of lubricant (sodium dodecyl sulfate) per 100 pbw of nitroxoline. Furthermore, as evidenced by Mao et al ([0070], it is known in the art that sodium dodecyl sulfate and instant sodium stearyl fumarate are equivalently or interchangeably used as lubricants in table dosage forms. It would be obvious to one skilled in the art to use 0.8-13.3 pbw of sodium stearyl fumarate as a lubricant in the pharmaceutical composition of claim 1 of App.’521 with a reasonable expectation of success.
With respect to instant limitation as to glidant being sodium dodecyl sulfate and the lubricant and the glidant being present together in the amount of 2.5-4 pbw per 100 pbw of the active pharmaceutical ingredient, as already discussed above, the composition of claim 1 of App.’521 also contains 0.8-13.3 pbw of instant glidant (sodium dodecyl sulfate) per 100 pbw of nitroxoline. Thus, the amount for the lubricant (sodium stearyl fumarate as discussed above) and glidant (sodium dodecyl sulfate) together would be 1.6-26.6 pbw per 100 pbw of nitroxoline. Such range overlaps with instant range 2.5-4 pbw for the amount of lubricant and glidant together, thus rendering instant range prima facie obvious. In re Wertheim, supra.
Instant limitation as to the film coating agent being HPMC and being present in the amount of 9-13 mass% relative to the mass of the uncoated pharmaceutical composition was already discussed in Paragraph 7 above while discussing instant claim 5.
Thus, claims 1 and 3 of App.’521 in view of Mao et al render obvious instant claim 6.
Response to Arguments
Applicant state that they have discovered that nitroxoline having D90 of 10-100 mm affords nitroxoline tablets with a moderate dissolution rate (i.e., the dissolution rate within 60 min being more than 75%). Applicant argue that although according to Chu and Han, the decreased particle size of the drug result in an increase in the dissolution rate, in the comparison between present Experimental Example 2 (D90 = 70.58 mm) and Comparative Example 1 (D90 = 8.037 mm which is outside the claimed range of 10-100 mm), the dissolution rate at 60 min of the two examples were 97% and 70.7%, respectively (as shown in Chen’s first 132 Declaration). Applicant thus argue that they demonstrated that the decreased particle size of nitroxoline resulted in a slower dissolution rate, contrary to the teachings of Chu and Han. Applicant also point to Chen’s second 132 declaration and argue that the additional supplementary experiments (Examples 10-15 using nitroxolines having different D90s) demonstrated the criticality of the claimed range 10-100 mm for the D90 of nitroxoline: the declaration states that when D90 of nitroxoline is within the claimed range 10-100 mm (such as 13.4, 50.7, 76.0 or 84.7 mm in Examples 10-13), the dissolution rates are all ≥ 75% at 60 min. As to Example 14 (D90 = 121.2 mm) and Example 15 (D90 = 122.4 mm), the declaration states that although their dissolution rates are also ≥ 75% at 60 min, the particles exhibited deteriorated fluidity (as indicated by the Carr Index of 26 and 29, respectively) and poor compressibility (as indicated by the Hsusner Ratio of 1.36 and 1.41, respectively) during the preparation process, thus making them unsuitable for commercial production. Applicant thus argue that controlling particle size should account not only for achieving an appropriate dissolution rate but also for factors important for commercial production, such as fluidity and compressibility. Applicant thus argue that the criticality of the claimed range 10-100 mm for the D90 of nitroxoline have been clearly demonstrated, which has not been taught or suggested by the prior art, and thus cannot be obtained through routine skill in the art.
The Examiner disagrees. First of all, as already discussed above, as evidenced by Bojnanska, it is already known in the art that although a particle size reduction and an increase of the surface area are recommended to increase the dissolution rate of drugs in general, for some drugs (especially for those that are lipophilic in nature), particle size reduction can result in aggregation of the material. This causes a consequent reduction in the effective surface area of the drugs exposed to liquids and hence a reduction in their dissolution rate. That is, the improvement of solubility by particle size reduction/increase of the surface area ceases when the particle size reaches a particular value and beyond the particular value, the solubility of the drugs decreases. Thus, applicant’s showing that the decreased particle size of nitroxoline resulted in a slower dissolution rate is nothing unexpected. Secondly, even though applicant state that they have discovered that nitroxoline having D90 of 10-100 mm affords nitroxoline tablets with a moderate dissolution rate (i.e., the dissolution rate within 60 min being more than 75%), the table shown in Chen’s second 132 declaration actually indicates that their nitroxoline tablets of Examples 10-13 formed from nitroxoline having D90 of 10-100 mm show a rapid dissolution: at both 30 min and 45 min, the dissolution rates are well above 75%, and present specification clearly states (see pg.16, lines 6-7) that the relatively rapid dissolution of an immediate-release formulation generally means that the dissolution rate at 30 min or 45 min is more than 75%. Furthermore, present Figure 1 also shows that for the nitroxoline tablets of present Examples 1-3 (formed from nitroxoline with D90 of 99.31mm, 70.58 mm and 42.55 mm), the dissolution rate at 30 min or 45 min is more than 75%, thus showing rapid dissolution. Thirdly, applicant’s argument that the Carr Index values and Hsusner Ratio values of Examples 14 and 15 indicate poor fluidity and poor compressibility (for the nitroxoline particles with D90 values larger the higher end of the claimed range) is not found to be persuasive because the Carr Index and Hsusner Ratio values (as shown in Chen’s second 132 declaration) are for granules of Examples 10-15 not for the nitroxolines themselves that are used for forming the granules (the 3rd page of Chen’s second 132 declaration states “Carr Index and Hsusner Ratio of the nitroxoline total mixed granules of Examples 10-15 . . .”). As stated in Chen’s second 132 declaration, after the nitroxoline, starch, lactose, starch (for pulping) and low substituted hydroxypropyl cellulose are mixed together, the mixture is subjected to wet granulation and wet milling, followed by a drying step and then a dry milling step. Sodium dodecyl sulfate is then added to form the final granules. Since applicant have two milling steps, applicant have chance to control the final granule size and could have made the final granules to have any reasonable specific particle size, and thus the Examiner does not understand why applicant are presenting the Carr Index and Hsusner Ratio values for the granules (and not for the nitroxolines used for forming the granules). The fluidity and compressibility are closely related to particle size, and since the Carr Index values and Hsusner Ratio values obtained for Examples 14 and 15 are for the granules and not for the nitroxolines (that were used for forming the granules), applicant have not actually shown that nitroxoline particles with larger D90 values (such as 121.2 mm and 122.4 mm) exhibited deteriorated fluidity and compressibility during the preparation process.
Therefore, for the reasons explained above, instant 103 rejections over Pan in view of Eivaskhani, Rigassi-Dietrich, Bykov, Chu and Bojnanska still stand.
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/SIN J LEE/
Primary Examiner, Art Unit 1613
October 4, 2026
