DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 23 June 2026, has been entered.
Status of Claims
Claims 1, 5, 7, 9, and 11-12 are amended.
Claim 18 is cancelled.
Claims 1-3, 5, 7-12, 14, 16-17, and 19-20 are pending and under consideration in the instant Office Action.
Objections Withdrawn
Objections to Claims
Applicant’s amendment to claim 5 has overcome the objection to the claim set forth in the Office Action mailed on 10 April 2026. Accordingly, the relevant objection is withdrawn.
Rejections Withdrawn
Rejections pursuant to 35 U.S.C. § 103
The rejection of claims 1-3, 5, 7-12, 14, 16-17, and 19-20 under 35 U.S.C. § 103 is withdrawn and made anew below. The rejection of claim 18 under 35 U.S.C. § 103 is rendered moot in view of Applicant’s cancellation of the claim.
Double Patenting Rejections
The nonstatutory double patenting (NSDP) rejection of claims 1-3, 5, 7-12, 14, 16-17, and 19-20 is withdrawn and made anew below. The NSDP rejection of claim 18 is rendered moot in view of Applicant’s cancellation of the claim.
New Grounds of Objection
Claim Objections
Claims 1 and 7 are objected to because of the following informalities:
Claims 1 and 7 were amended to recite a limitation regarding a dissolution rate. The conjunction “and” should appear before the limitation in each claim (e.g., the antepenultimate line of claim 1 should read “magnesium stearate; and”) (bold added for emphasis).
Claims 1 and 7 also both recite “10 min dissolution≤65%” and “60 min dissolution≥80%” in the final two lines of each claim. A space should follow the word “dissolution” in each instance (i.e., “dissolution ≤65%”).
Appropriate correction is required.
New Grounds of Rejection
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, 5, 7, 9-10, 12, 16, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Bykov et al. (Russia Patent No. RU 2149632 C1, provided by Applicant in the IDS filed on 2 May 2022, published on 27 May 2000, hereafter referred to as Bykov) as evidenced by Evonik Industries (Aerosil Pamphlet, published July 2015, accessed 31 January 2025) in view of Aly (J. Drug. Del. Sci. Tech. 2006, 16 (2), 151.).
Bykov teaches a pharmaceutical composition in the form of a coated tablet containing the active pharmaceutical ingredient nitroxoline (Abstract). The core of said tablet is taught to contain nitroxoline at 38-62% of the total composition weight, starch at 12-30% by weight, and slipping substances, which are interpreted as being equivalent to lubricants, at 1-4% by weight (Abstract, claim 1, example 1). The starch is taught to act as a filler accounting for 12-30% by weight of the composition and is additionally taught to act as a binder during composition mixing (pg. 2, antepenultimate para.). The quantity of starch used as a binder is 5-10% by weight of the total mass of starch, resulting in 0.6-3.0% by weight of starch as a binder (pg. 2, antepenultimate para.). Milk sugar, which is interpreted to be equivalent to lactose, is also taught to be a filler and is present in an amount of 12-30% w/w (claim 1, Example 1).
Bykov also teaches that the disintegrating agent polyvinylpyrrolidone may be used at 0.5-2.6% by weight in the composition, but on the exterior of the tablet rather than in the core (claim 2). Aerosil® is included in the core of the composition at 1-10% by weight and, in view of the disclosure from Evonik Industries is interpreted as equivalent to the core comprising a disintegrating agent as recited by the instant invention. The inclusion of Aerosil®, along with other excipients, is taught to modify the rate of API release following administration (pg. 2, para. 6 and 10).
Bykov further teaches coating the nitroxoline tablet with “sugar, basic magnesium carbonate, Aerosil®, talc, titanium dioxide, polyvinylpyrrolidone, dye and glossy substances” (claim 1). The coating taught by Bykov improves the taste of the composition while maintaining a strong, protective shell (pg. 2, antepenultimate para.) and maintains shelf stability for “more than 4 years” (pg. 2, penultimate para.). Following dissolution of the coating, Bykov teaches that the active substance is rapidly absorbed in the gastrointestinal tract, and the coating is therefore interpreted to be gastric-soluble (pg. 2, para. 12). The tablets in Example 1 gain 0.013 g following coating, increasing from an average mass of 0.187 g to 0.2 g, for a ~7% weight gain.
Guidelines on the obviousness of similar and overlapping ranges, amounts, and
proportions are provided in MPEP § 2144.05. With respect to claimed ranges which
“overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). These guidelines apply to the amounts of nitroxoline, filler, disintegrating agent, binder, and lubricant in the instant application. In each instance, the recited ranges either significantly overlap with or fall within the ranges taught by Bykov.
Bykov does not teach sodium dodecyl sulfate as a lubricant. This deficiency is offset by the teachings of Aly.
Aly teaches the parameter “resistance to compression index (RCI)” and its use in evaluating the efficacy of lubricants in pharmaceutical tableting (Title and Abstract). Magnesium stearate, a commonly used lubricant, was found to have the smallest RCI value and was subsequently used as a reference lubricant (Abstract). Aly also made note that hydrophobic lubricants, including magnesium stearate, can form films around substrate particles and that these films can “negatively affect the hardness of the compacts produced from the powder [formulation]” (pg. 151, left col., para. 1). Utilizing different tablet formulations, tableting the formulations, and subsequently dissolving the formed tablets, Aly compared the lubrication efficacy of stearic acid, sodium lauryl sulfate (another name for sodium dodecyl sulfate), and talc relative to magnesium stearate (Abstract and 2. Methods). Aly concluded that in mixes that are compressed to form tablets, sodium lauryl sulfate had the highest lubrication efficacy (Abstract and Table IV).
It would have been prima facie obvious to a person of ordinary skill in the art, prior to the filing of the instant application, in view of the teachings of Aly to use sodium lauryl sulfate as a lubricant in the invention of Bykov because combination of components known in the prior art in similar inventions to impart a known benefit yields predictable results. Bykov teaches a pharmaceutical composition in the form of a solid tablet comprising nitroxoline as an API in an amount from 38-62% w/w, starch as a filler in an amount from 12-30% w/w and a binder in an amount from 0.6-3% w/w, polyvinylpyrrolidone as a disintegrating in an amount from 0.5-2.6% w/w, slipping substances, which are interpreted as being equivalent to lubricants, in an amount from 1-4% w/w, and lactose as a filler in an amount from 12-30% w/w, quantities that render obvious the ranges recited in the instant application. Additionally, Bykov teaches coating the solid pharmaceutical tablet in a gastric-soluble premix that results in a ~7% weight gain, but does not teach specific slipping substances. In view of the teachings of Aly, an ordinary artisan would be motivated to use sodium lauryl sulfate as a lubricant because Aly teaches it to be efficacious in lubricating tableted pharmaceutical compositions. Further, because Bykov teaches that a lubricant should be used but does not teach a specific species, the teachings of Aly regarding the inclusion of sodium lauryl sulfate would provide missing information required to enable the invention.
The teachings of Bykov and Aly render obvious a pharmaceutical composition in the form of a solid tablet comprising nitroxoline as an API in an amount from 38-62% w/w, starch as a filler in an amount from 12-30% w/w and a binder in an amount from 0.6-3% w/w, polyvinylpyrrolidone as a disintegrating in an amount from 0.5-2.6% w/w, sodium lauryl sulfate as a slipping substance in an amount from 1-4% w/w, lactose as a filler in an amount from 12-30% w/w, and a gastric-soluble premix coating that results in a ~7% weight gain, identical to the claimed composition. Therefore, the composition Bykov and Aly would necessarily have a dissolution rate of 10 min dissolution <65%, and 60 min dissolution >80% as recited in claims 1 and 7.
The dissolution properties of the pharmaceutical composition recited in claims 1 and 7 arise from the composition of the invention, as evidenced by Tables 2-3, Examples 2 and 6, and Fig. 3 of the instant spec. In brief, Table 2 and Example 2 demonstrate that compositions comprising magnesium stearate (formulas 1-7) result in undesirable “aging” and that substituting magnesium stearate for stearic acid (formula 8), sodium stearyl fumarate (formula 9), or sodium dodecyl sulfate (formulas 10-13) alleviate the issue, with sodium dodecyl sulfate being preferred (instant spec. pg. 12, lines 25-26). Example 6, Table 3, and Fig. 3 demonstrate that the recited dissolution properties arise from the presence and concentration of sodium dodecyl sulfate. In lines 4-9 pg. 4 of the instant spec., it is summarized that “when sodium dodecyl sulfate is used as a lubricant, it simultaneously plays a dual role of lubrication and solubilization, which can successfully solve the technical difficulty” related to composition aging and disintegrating. Therefore, because the teachings of Bykov and Aly have rendered obvious a composition identical to the claimed composition, and thus, the composition of Bykov and Aly would necessarily have a dissolution rate of 10 min dissolution <65%, and 60 min dissolution >80% the recited dissolution properties would inherently be present.
Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). See MPEP § 2112.01. The court stated that a proper finding of inherency does not require that all limitations are taught in a single reference, and that inherency may meet a missing claim limitation when the limitation is "the natural result of the combination of prior art elements" (emphasis in original). Persion Pharms. LLC v. Alvogen Malta Operations LTD., 945 F.3d 1184, 1191, 2019 USPQ2d 494084 (Fed. Cir. 2019). See MPEP § 2112.IV. Because the recited limitation regarding dissolution is the natural result of the combination of prior art elements, the limitation is inherent and rendered obvious.
Claims 16 and 20 are interpreted as product-by-process claims. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). See MPEP § 2113. The patentability of instant claims 16 and 20 is determined by the product recited in claim 1, which was rendered obvious by the teachings of Bykov and Aly, therefore claims 16 and 20 are also prima facie obvious. As a result, there is a reasonable expectation of success in arriving at the invention of instant claims 1-2, 5, 7, 9-10, 12, 16, and 20 in view of the teachings of Bykov and Aly.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Bykov (Russia Patent No. RU 2149632 C1, provided by Applicant in the IDS filed on 2 May 2022, published on 27 May 2000) as evidenced by Evonik Industries (Aerosil Pamphlet, published July 2015, accessed 31 January 2025) in view of Aly (J. Drug. Del. Sci. Tech. 2006, 16 (2), 151.) as applied to claims 1-2, 5, 7, 9-10, 12, 16, and 20 above, and further in view of Jordan (U.S. Patent No. 5,885,617 A, priority to 6 June 1995).
Bykov and Aly teach the above.
Bykov and Aly do not teach the coating to comprise polyvinyl alcohol (PVA). This deficiency is offset by the teachings of Jordan.
Jordan teaches a moisture barrier film composition that can be used to coat pharmaceutical tablets (Abstract). During storage, Jordan teaches that solid pharmaceutical compositions may undergo degradation due to atmospheric moisture and that special packaging is sometimes required to mitigate the moisture (col. 1, lines 13-19). However, specialized packaging can be ineffective in humid climates, and Jordan teaches that similar protection may be achieved by “coating with materials which reduce the rate at which the dosage form absorbs atmospheric moisture” (col. 1, lines 23-28).
To achieve the goals above, Jordan teaches a coating composition comprising polyvinyl alcohol (PVA), soya lecithin, and optionally a flow aid, colorant, and suspending agent, which can be dispersed in water and subsequently be applied to solid pharmaceutical tablets (col. 1, lines 53 – col. 2, line 7 and claims 1 and 18). PVA is taught to impart excellent moisture barrier properties without requiring heating of the coating composition (col. 2, lines 38-45). The flow aid is taught to be talc, fumed silica, lactose, or starch (col. 2, line 46). In some embodiments, the suspending agent may be hydroxypropyl methylcellulose or hydroxypropyl cellulose, and acts as a viscosity modifier that stabilizes the composition (col. 2, lines 59-65 and claims 1 and 16-17). Finally, the colorant is taught to be food approved colors or dyes such as aluminum lakes, iron oxides, or TiO2, and in one embodiment is tartrazine aluminum lake (col. 2, lines 47-50, Example 10, and claims 12, 17, and 29-31).
It would have been prima facie obvious to a person of ordinary skill in the art, prior to the filing of the instant application, to use the moisture barrier coating taught by Jordan in the invention rendered obvious by the teachings of Bykov and Aly because the use of a known technique to improve a known product for which the technique was designed produces predictable results. The teachings of Bykov and Aly rendered obvious a solid pharmaceutical composition comprising nitroxoline as an API, starch as a filler and binder, polyvinylpyrrolidone as a disintegrating agent, sodium lauryl sulfate as a lubricant, and lactose as a filler, in quantities that either encompass or overlap with the ranges recited in the instant application, which is coated in a gastric-soluble coating premix. In view of the teachings of Jordan, an ordinary artisan would be motivated to use the moisture barrier film composition on the solid pharmaceutical tablet rendered obvious by Bykov and Aly because Jordan teaches their PVA-containing composition to protect pharmaceutical tablets from degradation via atmospheric moisture. One of ordinary skill would find it desirable to protect their invention from degrading prior to reaching the consumer and to extend its shelf-life via increased protection. As a result, there is a reasonable expectation of success in arriving at the invention of claim 3 in view of the teachings of Bykov and Aly and further in view of the teachings of Jordan.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Bykov (Russia Patent No. RU 2149632 C1, provided by Applicant in the IDS filed on 2 May 2022, published on 27 May 2000) as evidenced by Evonik Industries (Aerosil Pamphlet, published July 2015, accessed 31 January 2025) in view of Aly (J. Drug. Del. Sci. Tech. 2006, 16 (2), 151.) as applied to claims 1-2, 5, 7, 9-10, 12, 16, and 20 above, and further in view of Cheng (U.S. Patent Application Publication No. US 2017/0065528 A1, published on 9 March 2017).
Bykov and Aly teach the above.
Bykov and Aly do not teach the weight gain of the coating to be 9-12% w/w. This deficiency is offset by the teachings of Cheng.
Cheng teaches an enteric film coating for drugs that imparts alcohol resistance and inhibits dose “dumping” (Abstract and para. [0001]). Drug “dumping” is taught to be a premature or exaggerate release of a drug from a pharmaceutical composition in a confined area that can result in “adverse physiological effects and, in extreme cases, drug-induced toxicity” (para. [0002]). This phenomenon is typically seen with drugs taken orally when in the gastrointestinal tract alongside alcohol (para. [0003-0004]). The goal of the invention of Cheng is to provide an alcohol resistant enteric drug coating “to ensure there is no change in the bioavailability of an API in the presence of alcohol in the GI tract” (para. [0009]).
To achieve this goal, Cheng teaches the use of a coating comprising an aqueous solution of a salt of alginic acid, a shellac, and an additive that may be a detackifier, slip aid, surfactant, plasticizer, preservative, opacifier, colorant, and combinations thereof (para. [0012] and [0036] and claims 1 and 8). The combination of alginate salt, shellac, and additive(s) produces a coating that does not rupture or disintegrate in the stomach (pH of ≤1.2), has limited API release over 2 hours in the stomach, has resistance to alcohol at low pH, and does release API at pH >4.5, the pH of the small intestine (para. [0062]). To achieve this result, Cheng teaches that the coating weight gain on a solid pharmaceutical tablet should be ≤15% w/w, or preferably between 1-10% w/w (para. [0078] and claim 17). This goal is validated in Example 5 and the bio-simulation tests presented in Tables 8-9.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the filing of the instant application, to combine the coating taught by Cheng with the solid pharmaceutical tablets rendered obvious by the teachings of Bykov and Aly to arrive at the invention of claim 8 because combining prior art elements according to known methods yields predictable results. The teachings of Bykov and Aly rendered obvious a solid pharmaceutical composition comprising nitroxoline as an API, starch as a filler and binder, polyvinylpyrrolidone as a disintegrating agent, sodium lauryl sulfate as a lubricant, and lactose as a filler, in quantities that either encompass or overlap with the ranges recited in the instant application, which is coated in a gastric-soluble coating premix. In view of the teachings of Cheng, an ordinary artisan would be motivated to combine the coating comprising an alginate salt and shellac for a weight gain of 1-10% with the composition rendered obvious above because Cheng teaches this coating to prevent drug “dumping”, which can lead to adverse side effects. An ordinary skill in the art would desire their pharmaceutical composition to deliver the API in the intended quantity in the proper portion of the GI tract and would not desire any adverse effects related to drug dumping and would therefore be motivated to use a coating that can mitigate these potential issues. As a result, there is a reasonable expectation of success in arriving at the invention of claim 8 in view of the teachings of Bykov and Aly and further in view of the teachings of Cheng.
Claims 11 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Bykov (Russia Patent No. RU 2149632 C1, provided by Applicant in the IDS filed on 2 May 2022, published on 27 May 2000) as evidenced by Evonik Industries (Aerosil Pamphlet, published July 2015, accessed 31 January 2025) in view of Aly (J. Drug. Del. Sci. Tech. 2006, 16 (2), 151.) as applied to claims 1-2, 5, 7, 9-10, 12, 16, and 20 above, and further in view of Grillo et al. (U.S. Patent No. 6,468,561 B1, priority to 30 June 1997, hereafter referred to as Grillo).
Bykov and Aly teach the above.
Bykov and Aly do not teach the coating to comprise polyethylene glycol (PEG), hydroxypropyl methylcellulose, or lake. This deficiency is offset by the teachings of Grillo.
Grillo teaches aqueous film coatings, which may be applied to solid pharmaceutical tablets or other substrates, which provide improved properties (Title and Abstract). Cellulose polymers, such as hydroxypropyl methylcellulose, are taught to be widely used in pharmaceutical tablet coatings, but difficulties can arise when using cellulosic materials, such as adherence issues, particularly if the matrix comprising the API(s) is waxy (col. 1, lines 20-32). In addition, Grillo teaches that sugar is often used for flavor in coatings, but efforts are being made to replace sugar to reduce calories and harm to teeth, and that cellulosic polymers meet these needs but tend to “produce coatings that have undesirable taste and mouth-feel” (col. 1, lines 33-42).
To meet the goal of a coating with desirable adhesive qualities and taste, low calorie count, and reduced danger to teeth, Grillo teaches aqueous film coatings that are based on polydextrose and may contain additional polymers, plasticizers, colorants and detackifiers (col. 1, line 46 – col. 2, line 40 and claims 1-2). The additional polymer may be hydroxypropyl methylcellulose, which is taught to be “particularly adapted for coating waxy matrix tablets, which are particularly difficult to coat”, and/or hydroxypropyl cellulose (col. 2, lines 42-62, Examples 7-11, and claim 16). The plasticizer is in some embodiments a polyethylene glycol (col. 2, line 63, Examples 1-15, and claims 3, 11-12, 22, and 43). Finally, the colorant may be selected from FD&C lakes, D&C lakes, TiO2, or other dyes, and in some embodiments may be FD&C Yellow #5 aluminum lake (col. 2, line 66 - column 3, line 3, Examples 3-5, 7, 15, and 17-18, and claims 9, 11-12, 26, 41, and 55). The coating compositions above are taught by Grillo to be “especially effective in coating tablets and the like having debossed or intaglio logos, trademarks, designs or words thereon since it adheres to the tablet surfaces without bridging and obscuring the debossed or intaglio printing” (col. 3, lines 11-15).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the filing of the instant application, to combine the coating taught by Grillo with the solid pharmaceutical tablets rendered obvious by the teachings of Bykov and Aly to arrive at the invention of claim 14 because combining prior art elements according to known methods yields predictable results. The teachings of Bykov and Aly rendered obvious a solid pharmaceutical composition comprising nitroxoline as an API, starch as a filler and binder, polyvinylpyrrolidone as a disintegrating agent, sodium lauryl sulfate as a lubricant, and lactose as a filler, in quantities that either encompass or overlap with the ranges recited in the instant application, which is coated in a gastric-soluble coating premix. In view of the teachings of Grillo, an ordinary artisan would be motivated to combine PEG, hydroxypropyl methylcellulose, and lake with the coating premix taught by Bykov, and replace sugar in the coating of Bykov with polydextrose, because Grillo teaches those coating composition components to reduce the calorie count and damage to teeth of the consumer while improving the adherence to the composition matrix. Further, Grillo teaches that their coating composition allows for logos, designs, or other writing on the exterior of the pharmaceutical tablet, which an ordinary artisan would desire to identify and distinguish their product to consumers.
Although Grillo does not teach hydroxypropyl cellulose to be a disintegrating agent, Grillo does teach its inclusion in the coating above and its properties as a disintegrating agent are necessarily present. See MPEP § 2112.01. “Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). “A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.” As a result, there is a reasonable expectation of success in arriving at the invention of claims 11 and 14 in view of the teachings of Bykov and Aly and further in view of the teachings of Grillo.
Claims 17 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Bykov (Russia Patent No. RU 2149632 C1, provided by Applicant in the IDS filed on 2 May 2022, published on 27 May 2000) as evidenced by Evonik Industries (Aerosil Pamphlet, published July 2015, accessed 31 January 2025) in view of Aly (J. Drug. Del. Sci. Tech. 2006, 16 (2), 151.) as applied to claims 1-2, 5, 7, 9-10, 12, 16, and 20 above, and further in view of Shim et al. (J. Nat. Canc. Inst. 2010, 102 (24), 1855., hereafter referred to as Shim).
Bykov and Aly teach the above.
Bykov and Aly do not teach the use of solid pharmaceutical compositions comprising nitroxoline to treat bladder cancer. This deficiency is offset by the teachings of Shim.
Shim teaches the efficacy of nitroxoline in inhibiting angiogenesis and growth of human cancer cells (Abstract). Following high throughput screening of compounds against type 2 methionine aminopeptidase (MetAP2), a protein associated with angiogenesis in tumors, nitroxoline was identified as a promising inhibitor candidate of the angiogenesis and growth of human cancers (pg. 1856 and pg. 1861, Target-Based Screening). Nitroxoline displayed dose-dependent MetAP2 inhibition and endothelial cell proliferation inhibition against human umbilical vein endothelial cells (HUVEC) via assays performed in cell cultures (pg. 1862-1863, Figures 1 and 2). A three-dimensional assay against HUVEC tube formation further demonstrated dose-dependent inhibition by nitroxoline (pg. 1868, Figure 6).
Following successful inhibition in vitro, nitroxoline was analyzed in vivo using mouse models implanted with recombinant mouse vascular endothelial growth factor 164 (VEGF164), human breast tumor xenografts, and human bladder tumor xenografts (pg. 1868-1871). Mice were injected with 60 mg/kg each day, for 7 days following implantation of VEGF164 and 30 days following human breast tumor xenografts, in a vehicle of 5% DMSO in peanut oil (pg. 1860, left col., para. 2 - right col., para. 3). Against both the endothelial growth factor and breast cancer implants, nitroxoline displayed effective inhibition of proliferation and tumor growth (pg. 1868, left col., para. 2 - pg. 1870, right col., para. 1). Mice implanted with bladder cancer tumors were administered nitroxoline in the vehicle described above at a dose of 30 mg/kg/day for 2 weeks and displayed “a statistically significant inhibition of tumor growth compared with the vehicle-treated mice”.
Shim concludes that nitroxoline displays effective “blocking [of] angiogenesis and cancer xenograft growth, particularly in a bladder cancer model” using mouse models (pg. 1871, left col., para. 2). Further, the “efficacy of nitroxoline in inhibiting both angiogenesis and bladder cancer xenograft growth in vivo calls for further preclinical and clinical evaluation of nitroxoline in the treatment of bladder carcinomas” (pg. 1872, left col., para. 1-2).
It would have been prima facie obvious to a person of ordinary skill in the art, prior to the filing of the instant application, in view of the teachings of Shim to use the invention rendered obvious by the teachings of Bykov and Aly in a method of treating bladder cancer because using a known active pharmaceutical ingredient in a method to treat a condition it is known to treat produces predictable results. The teachings of Bykov and Aly rendered obvious a solid pharmaceutical composition comprising nitroxoline as an API, starch as a filler and binder, polyvinylpyrrolidone as a disintegrating agent, sodium lauryl sulfate as a lubricant, and lactose as a filler, in quantities that either encompass or overlap with the ranges recited in the instant application, which is coated in a gastric-soluble coating premix. In view of the teachings of Shim, one of ordinary skill would be motivated to use the composition above in a method to treat bladder cancer because Shim teaches the API nitroxoline to be effective in treating such a condition. The ordinary artisan would desire an application for their pharmaceutical composition and Shim teaches that the nitroxoline-containing composition would display efficacy in treating bladder cancer. As a result, there is a reasonable expectation of success in arriving at the method of instant claims 17 and19 in view of the teachings of Bykov and Aly and further in view of the teachings of Shim.
Response to Arguments
The Applicant’s arguments, filed on 23 June 2026, have been fully considered but are not persuasive.
NOTE: Applicant refers to a release rate of nitroxoline from their composition throughout these remarks. It is noted that a “release rate” is not recited anywhere in the instant claims. For the sake of consistency with instant claims 1 and 7, the release rate is interpreted as being equivalent to the recited dissolution rate.
In response to applicant's arguments against the references individually from the final para. of pg. 9 to para. 4 of pg. 11, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In the final para. of pg. 9, Applicant argues that Bykov uses nitroxoline as an antibacterial agent rather than an anticancer agent as in instant claims 17 and 19. This is not a persuasive argument against nonobviousness because, as stated in the rejection above, the use of a pharmaceutical composition comprising nitroxoline to treat cancer is obvious in view of the teachings of Shim. In brief, Shim teaches that nitroxoline blocks angiogenesis and cancer xenograft growth, particularly in a bladder cancer model, and its efficacy encouraged further preclinical and clinical evaluation in the treatment of bladder carcinomas (vide supra).
Applicant also argues in this para. that the release rate of the invention taught by Bykov is faster than the claimed invention, analyzes the data disclosed by Bykov, and concludes that the reference does not teach a moderate release rate. This argument is not found to be persuasive because the rejection of claims 1 and 7, which recite a dissolution rate, states that the claimed invention is obvious in view of the teachings of Bykov and Aly, not upon the teaching of the Bykov reference alone, and the obvious invention would inherently possess the claimed dissolution rate (vide supra). An argument against one reference individually is not a persuasive demonstration of nonobviousness when the rejection was based upon the combination of the two references.
In para. 3 of pg. 10, Applicant argues that because the API nitroxoline has been known in the art since the 1960s and the references used in previous Office Actions “only found that the closest prior art still has the indication for anti-infection purposes” that “seeking a nitroxoline tablet with an appropriate release rate in the anticancer field is a technical challenge that the field has long aspired to solve but has failed to do”. None of these arguments are directed to the rejections under 35 U.S.C. § 103 presented in the previous Office Actions and are therefore considered moot.
In the antepenultimate and penultimate para. of pg. 10, Applicant argues that the Li reference does not address the same technical problem as the instant application, does not provide an indication that a skilled artisan would seek an auxiliary material to reduce dissolution rates, and does not provide experimental data to motivate the replacement of magnesium stearate with sodium lauryl sulfate to achieve a moderate release rate. The new grounds of rejection above do not cite the Li reference and the arguments are considered moot. Applicant is advised, however, that the motivation for modifying a reference need not be for the same purpose or to solve the same problem (see MPEP § 2144.IV.) and that a “reference is analogous art to the claimed invention if: (1) the reference is from the same field of endeavor as the claimed invention (even if it addresses a different problem)” (bold added for emphasis) (see MPEP § 2141.01(a).). The arguments in the para. spanning the bottom of pg. 10 and top of pg. 11 are also directed to the Li reference. In view of the new grounds of rejection above, which do not cite the teachings of Li, the arguments are considered moot.
Finally, from para. 2-4 of pg. 11 Applicant argues that their invention recites “specific content of each components, especially for the lubricant, which is further non-obvious”. The guidelines on the obviousness of similar and overlapping ranges, amounts, and proportions are provided in MPEP § 2144.05 and summarized above. If Applicant is intending to demonstrate the criticality of the recited ranges to support a claim of unexpected results, guidelines can be found in MPEP § 716.02. To demonstrate that results are unexpected and significant, the Applicant has the responsibility of presenting evidence that establishes “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.” Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). “Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims”. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e).
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 1-3, 5, 7-12, 14, 16-17, and 19-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of copending Application No. 17/757,801 in view of Bykov (Russia Patent No. RU 2149632 C1, published on 27 May 2000), Grillo (U.S. Patent No. 6,468,561 B1, priority to 30 June 1997), and Shim (J. Nat. Canc. Inst. 2010, 102 (24), 1855.).
This is a provisional nonstatutory double patenting rejection.
Copending Application No. 17/757,801 recites a pharmaceutical composition in claim 1 that comprises nitroxoline as an API, a filler that may be starch or lactose, a binder than may be hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, or starch, a disintegrant that may be hydroxypropyl cellulose, a lubricant that may be magnesium stearate, sodium stearyl fumarate, or sodium dodecyl sulfate, a glidant that may be silica or talc, and a film coating agent which may be hydroxypropyl methylcellulose and/or PVA. The nitroxoline is recited as being present in an amount of 20-65% w/w based on the total weight of the pharmaceutical composition, the filler is present in an amount 6-180% w/w based on the total weight of the pharmaceutical composition, the binder is present in an amount of 0-65% w/w based on the total weight of the pharmaceutical composition, not including 0%, the disintegrant is present in an amount of 0-65% w/w based on the total weight of the pharmaceutical composition, not including 0%, the lubricant is present in an amount 5x10-4-12% w/w, the glidant is present in an amount of 0-13% w/w based on the total weight of the pharmaceutical composition, not including 0%, and the coating is present in an amount that results in a 3-15% weight gain (claims 1-4).
Copending Application No. 17/757,801 does not recite the pharmaceutical composition coating to comprise TiO2, talc, polyethylene glycol, or lake nor the pharmaceutical composition to be used to treat bladder cancer. These deficiencies are offset by the teachings of Bykov, Grillo, and Shim.
Bykov, Grillo, and Shim are described above.
It would have been prima facie obvious to a person of ordinary skill in the art, prior to the filing of the instant application, to modify the invention recited by ‘801 in view of the teachings of Bykov, Grillo, and Shim to arrive at the invention of instant claims 1-3, 5, 7-12, 14, 16-17, and 19-20 because combining prior art elements to impart known benefits yields predictable results. Copending application ‘801 recites a pharmaceutical composition that may comprise nitroxoline, sodium dodecyl sulfate, sodium stearyl fumarate, lactose, starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose in amounts that either encompass or significantly overlap with the ranges recited in the instant application. In view of the teachings of Bykov and Grillo, an ordinary artisan would be motivated to include Ti-O2, talc, PEG, and lake in the coating mixture of the composition recited in ‘801 because Bykov teaches that their coating improves the taste of the composition while maintaining a strong, protective shell that maintains shelf stability for “more than 4 years”, while Grillo teaches the inclusion of polydextrose, PEG, and lake to produce a coating that better adheres to the pharmaceutical composition and allows for logos, designs, or other writing on the exterior of the pharmaceutical composition. One of ordinary skill would desire a strong, shelf-stable coating that properly adheres to the pharmaceutical product and can display an identifiable logo or design to distinguish their product.
In addition, in view of the teachings of Shim, a person of ordinary skill would be motivated to use the invention rendered obvious above in a method of treating bladder cancer because Shim teaches the API nitroxoline to be effective in treating such a condition. The ordinary artisan would desire an application for their pharmaceutical composition and Shim teaches that the nitroxoline-containing composition would display efficacy in treating bladder cancer.
The invention recited by Application ‘801 in view of the teachings of Bykov and Aly renders obvious a pharmaceutical composition in the form of a solid tablet comprising nitroxoline as an API in an amount from 20-65% w/w, starch as a filler in an amount from 6-180% w/w and a binder in an amount from 0-65% w/w not including 0%, hydroxypropyl cellulose as a disintegrating in an amount from 0-65% w/w not including 0%, sodium lauryl sulfate as a lubricant in an amount from 5x10-4-12% w/w, lactose as a filler in an amount from 6-180% w/w, and a gastric-soluble premix coating that results in a 3-15% weight gain. Therefore, the composition recited in instant claims 1 and 7 is obvious in view of the invention recited by Application ‘801 and the teachings of Bykov and Aly.
The dissolution properties of the pharmaceutical composition recited in claims 1 and 7 arise from the composition of the invention (vide supra). Therefore, because the invention recited by Application ‘801 in view of the teachings of Bykov and Aly have rendered obvious a composition identical to the one recited in claims 1 and 7, the recited dissolution properties would inherently be present.
Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). See MPEP § 2112.01. The court stated that a proper finding of inherency does not require that all limitations are taught in a single reference, and that inherency may meet a missing claim limitation when the limitation is "the natural result of the combination of prior art elements" (emphasis in original). Persion Pharms. LLC v. Alvogen Malta Operations LTD., 945 F.3d 1184, 1191, 2019 USPQ2d 494084 (Fed. Cir. 2019). See MPEP § 2112.IV. Because the recited limitation regarding dissolution is the natural result of the combination of prior art elements, the limitation is inherent and rendered obvious.
Instant claims 16 and 20 are interpreted as product-by-process claims. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). See MPEP § 2113. The patentability of instant claims 16 and 20 is determined by the product recited in claim 1, which was rendered obvious by the invention recited by copending Application No. 17/757,801 and the teachings of Bykov and Grillo, therefore claims 16 and 20 are also prima facie obvious. As a result, there is a reasonable expectation of success in arriving at the invention of claims 1-3, 5, 7-12, 14, and 16-20 in view of the invention recited by copending Application No. 17/757,801 and in view of the teachings of Bykov, Grillo, and Shim.
Claims 1-3, 5, 7-12, 14, and 16-20 are directed to an invention not patentably distinct from claims 1-4 of commonly assigned copending application no. 17/757,801 in view of Bykov (Russia Patent No. RU 2149632 C1, published on 27 May 2000), Grillo (U.S. Patent No. 6,468,561 B1, priority to 30 June 1997), and Shim (J. Nat. Canc. Inst. 2010, 102 (24), 1855.). Specifically, see above.
The U.S. Patent and Trademark Office may not institute a derivation proceeding in the absence of a timely filed petition. The USPTO normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). Commonly assigned copending application no. 17/757,801, discussed above, may form the basis for a rejection of the noted claims under 35 U.S.C. 102 or 103 if the commonly assigned case qualifies as prior art under 35 U.S.C. 102(a)(2) and the patentably indistinct inventions were not commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention.
In order for the examiner to resolve this issue the applicant or patent owner can provide a statement under 35 U.S.C. 102(b)(2)(C) and 37 CFR 1.104(c)(4)(i) to the effect that the subject matter and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person. Alternatively, the applicant or patent owner can provide a statement under 35 U.S.C. 102(c) and 37 CFR 1.104(c)(4)(ii) to the effect that the subject matter was developed and the claimed invention was made by or on behalf of one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement; the application must also be amended to disclose the names of the parties to the joint research agreement.
A showing that the inventions were commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention will preclude a rejection under 35 U.S.C. 102 or 103 based upon the commonly assigned case. Alternatively, applicant may take action to amend or cancel claims such that the applications, or the patent and the application, no longer contain claims directed to patentably indistinct inventions.
Response to Arguments
In the section titled “Double Patenting” that spans pg. 11-12, Applicant argues that because the objections and rejections above should be withdrawn, the nonstatutory double patenting (NSDP) rejection would be the only remaining rejection and should therefore be withdrawn. The Examiner disagrees for at least the reasons detailed above.
A complete response to a NSDP rejection is either a reply by the Applicant showing that the claims subject to the restriction are patentably distinct from the reference claims, or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action (see MPEP § 1490 for a discussion of terminal disclaimers). Such a response is required even when the nonstatutory double patenting rejection is provisional.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sean J. Steinke, Ph.D., whose telephone number is (571) 272-3396. The examiner can normally be reached Mon. - Fri., 09:00 - 17:00 ET.
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/S.J.S./
Examiner, Art Unit 1619
/DAVID J BLANCHARD/Supervisory Patent Examiner, Art Unit 1619
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