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 .
Drawings Objection
The drawings Fig. 1, 4, 11, 15, 16, 17, 21, 22, 23, 24, and 25 are not of sufficient quality to permit examination. The current blurred/fuzzy drawing figures makes it difficult to reliably differentiate critical specific reference characters from one another (e.g., distinguishing "3" from "8", or "B" from "8"). This compromises the link between the drawings and the written description and directly impacts the clarity of the disclosure.
New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application because the text characters in the figures characters not sufficiently legible, due to low resolution lacking sufficient contrast and sharpness. The Examiner advises the applicant to replace all the drawing figures with high-resolution drawing figure replacement sheets, featuring clean, uniform, and distinct letters, numbers, graphs, and images that maintain legibility when reduced to 2/3 size for publication.
The applicant may correct this defect by submitting higher-resolution drawings (minimum 300 DPI) with clear, machine-printed text, ensuring all text labels comply with 37 CFR § 1.84 (e.g., font size ≥ 0.32 cm (1/8 inch) for characters). Failure to correct the figure may result in expungement of non-compliant drawings. The applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings.
Accordingly, replacement drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to this Office action. The replacement sheet(s) should be labeled “Replacement Sheet” in the page header (as per 37 CFR 1.84(c)) so as not to obstruct any portion of the drawing figures. If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action.
Applicant is given a shortened statutory period of TWO (2) MONTHS to submit new drawings in compliance with 37 CFR 1.81. Extensions of time may be obtained under the provisions of 37 CFR 1.136(a) but in no case can any extension carry the date for reply to this letter beyond the maximum period of SIX MONTHS set by statute (35 U.S.C. 133). Failure to timely submit replacement drawing sheets will result in ABANDONMENT of the application.
Status of the Claims
The listing of claims filed 21 October 2024, have been examined. Claims 1, 2, 6-9, 14, 17, 28, 29, and 48-61 are pending. Claims 1, 2, 9, 14, and 46 are amended, claims 3-5, 10-13, 15, 16, 18-27, 30-45, and 47 are canceled, and new claims 48-61 have been added.
Claim Objections
Claims 51, 53, and 59 are objected to because of the following informalities:
Claim 51 recites, "where the active agent...". This should read, "wherein the active agent...". Appropriate correction is advised.
Claim 53 recites, "The method of claim of claim 49...". This should read, "The method of claim 49...". Appropriate correction is required.
Claim 59 lacks a terminal period at the end of the text. Correction with the addition of a period is required to terminate the claim.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. § 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. § 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 49-61 are rejected under 35 U.S.C. § 112(a) or 35 U.S.C. § 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claims 49-61 are rejected because the specification, while being enabling for certain disclosed embodiments involving intravesical delivery of buoyant particles for selected urinary disorders, does not reasonably enable one of ordinary skill in the art to make and use the full scope of the claimed invention without undue experimentation, particularly with respect to the broadly claimed methods of preventing numerous unrelated ailments recited in the claims.
The determination of whether experimentation required to practice the claimed invention is undue has been made after consideration of the factors set forth in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988) and MPEP § 2164.01(a). Accordingly, consideration of each factor follows:
(1) Breadth of the Claims
The claims are exceptionally broad. Independent claim 49 broadly encompasses methods of treating and/or preventing an ailment merely by delivering buoyant controlled-release particles into the urinary bladder, without limitation regarding the identity of the active agent, dosage, therapeutic concentration, release kinetics required for efficacy, duration of administration, patient population, disease stage, disease etiology, mechanism of prevention, treatment protocol, or clinical endpoint.
Dependent claims limit the scope by encompassing prevention or treatment of urinary tract infection, bladder cancer, kidney cancer, ureter cancer, urethra cancer, anticoagulant disease, overactive bladder, underactive bladder, retained urine, diabetes, heart failure, kidney failure, and cystitis, using virtually any pharmacologically active agent, including anti-infectives, chemotherapeutics, RAAS inhibitors, anticoagulants, biologics, enzymes, urease inhibitors, contrast agents, kidney stone agents, anesthetics, analgesics, diuretics, and anti-inflammatory agents, with release periods extending beyond one month and substantially steady-state release. Still, the breadth of the claimed genus remains therefore immense, encompassing numerous unrelated diseases having entirely different etiologies, mechanisms of action, pharmacology, dosing requirements, and clinical endpoints. This factor weighs strongly in favor of non-enablement.
(2) Nature of the Invention
The invention concerns long-term intravesical controlled drug delivery for therapeutic and prophylactic use. While controlled-release drug delivery systems themselves are known, the claims extend beyond delivery technology to encompass methods of preventing numerous diseases. Preventive therapies generally require demonstrating that administration prior to onset of disease reduces disease incidence or risk in an at-risk population. Unlike treatment of existing disease, prevention requires establishing appropriate patient selection, prophylactic dosing, duration of administration, timing of administration, long-term safety, sustained efficacy, and acceptable risk-benefit ratio. The specification provides little guidance addressing these considerations. Moreover, several claimed diseases (e.g., diabetes, heart failure, kidney failure, kidney cancer) involve complex systemic pathophysiology rather than localized bladder pathology. Accordingly, the nature of the invention itself favors a finding that considerably more disclosure would be necessary to enable the full claimed scope.
(3) State of the Prior Art
The prior art recognizes intravesical administration for treatment of certain bladder disorders, particularly bladder cancer and urinary tract infections. However, the art does not establish that intravesical sustained-release administration generally prevents urinary tract infections, bladder cancer, kidney cancer, ureter cancer, urethral cancer, diabetes, heart failure, kidney failure, or numerous additional disorders recited throughout the claims. Nor does the prior art establish that simply retaining buoyant particles within urine inherently provides prophylactic efficacy against such diverse diseases. Consequently, one of ordinary skill would not have possessed a well-developed body of knowledge allowing routine extension of the disclosed embodiments to the full breadth of the claimed preventive methods. This factor weighs in favor of non-enablement.
(4) Level of Ordinary Skill in the Art
One of ordinary skill would likely possess expertise in pharmaceutical sciences, controlled drug delivery, urology, medicinal chemistry, biomaterials, or pharmaceutical formulation science. Although highly skilled, such a person could not reasonably predict prophylactic efficacy across the enormous number of diseases encompassed by the claims based solely upon the present disclosure. Even highly skilled artisans cannot substitute missing scientific teachings regarding disease prevention with routine experimentation. This factor therefore favors non-enablement.
(5) Level of Predictability in the Art
The pharmaceutical arts, particularly therapeutic efficacy and disease prevention, are generally regarded as unpredictable. Predictability is especially low regarding long-term controlled-release pharmacokinetics, prophylactic efficacy, optimal dosing, duration of exposure, patient-to-patient variability, prevention of cancer recurrence, prevention of recurrent infections, and prevention of chronic systemic diseases. Whether continuous intravesical administration of a given active agent will prevent disease cannot be reliably predicted merely from its therapeutic activity. For example, an antibiotic capable of treating an active urinary tract infection does not necessarily prevent recurrent infections over extended periods, an anti-neoplastic agent capable of treating bladder cancer does not necessarily prevent future cancer development, an RAAS inhibitor administered intravesically would not reasonably be expected to prevent heart failure or kidney failure absent substantial supporting evidence. Because therapeutic and prophylactic efficacy remain highly unpredictable, this factor weighs strongly toward non-enablement.
(6) Amount of Direction or Guidance Presented
Although the specification describes numerous possible active agents and particle designs, it provides only generalized guidance. The disclosure largely consists of broad lists of possible drugs, particle materials, buoyancy characteristics, release durations, and disease indications. The specification does not teach, for most claimed diseases effective dosage, therapeutic window, prophylactic dosage, duration of administration, frequency of administration, pharmacodynamic targets, biomarkers of prevention, patient selection criteria, and efficacy endpoints. With respect to prevention, the disclosure primarily states that embodiments "include methods of treating or preventing" disease and notes that patients may be "at risk" or have a history of urinary tract infections, but provides little technical teaching explaining how prevention is achieved or how preventive efficacy would be established. Accordingly, the specification provides insufficient guidance to permit the full claimed scope to be practiced without undue experimentation.
(7) Presence or Absence of Working Examples
The specification contains engineering discussion concerning particle construction, buoyancy, retention, degradation, and release. However, there are no working prophetic or experimental examples demonstrating prevention of the broad array of claimed ailments. Specifically absent are examples demonstrating prevention of recurrent UTI, prevention of bladder cancer, prevention of kidney cancer, prevention of ureter cancer, prevention of urethral cancer, prevention of diabetes, prevention of heart failure, and prevention of kidney failure. Likewise absent are animal studies or human clinical data demonstrating prophylactic efficacy. The lack of representative working examples spanning the breadth of the prevention claims weighs strongly in favor of non-enablement.
(8) Quantity of Experimentation Necessary
Practicing the full scope of the claims would require extensive research for each disease indication, including determination of suitable active agents, loading concentrations, release profiles, therapeutic dose, prophylactic dose, retention period, degradation profile, safety profile, pharmacokinetics, pharmacodynamics, efficacy in appropriate disease models, and long-term clinical outcomes. For prevention claims, additional experimentation would be required to determine which patients are at sufficient risk, when prophylactic administration should begin, duration of prophylaxis, whether disease incidence is actually reduced, whether chronic administration remains safe. Such work would require substantial preclinical studies and clinical trials rather than routine optimization. Accordingly, the experimentation required is undue.
In summary, after weighing all eight Wands factors, the Examiner concludes that the specification fails to enable the full scope of claims 49-61. In particular the claims encompass prevention of numerous unrelated diseases having widely different etiologies; the disclosure provides only generalized descriptions rather than disease-specific enabling teachings; preventive efficacy is highly unpredictable in the pharmaceutical arts; representative working examples are absent for the claimed preventive methods; and practicing the full breadth of the claims would require extensive independent research and clinical investigation amounting to undue experimentation.
Accordingly, claims 49-61 are rejected under 35 U.S.C. 112(a) as failing to comply with the enablement requirement. The disclosure does not enable a person of ordinary skill in the art to make and use the full scope of the claimed methods of treating and, particularly, preventing the recited ailments without undue experimentation.
Claim Rejections - 35 USC § 112(b)
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 Applicant regards as his invention.
Claims 28, 29, 46, 50, 57 and 58 are 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, regards as the invention.
Claims 28, 29, 57, and 58, are rejected as indefinite for lack of antecedent basis for recitation of "the pharmacologically active agent". The respective independent claims recite "an active agent." The scope of the claim is unclear because one of ordinary skill in the art cannot determine whether this term is intended to be synonymous with "the active agent" previously recited in the base claim, or whether it refers to a different element. This failure to particularly point out and distinctly claim the invention renders the claims indefinite (see MPEP § 2173.05(e)).
Claim 46 lacks antecedent basis for "the active agent" and should be "an active agent", since it is the first recitation in the claim and it has not been previously introduced in the claim, making the scope of the claim unclear. The claim positively recites "silver sulfadiazine" later, but the first instance of "the active agent" is grammatically and legally indefinite. Furthermore, "silver sulfadiazine" should be introduced as "and, wherein the active agent is 5 wt. % to 50 wt. % of silver sulfadiazine dispersed within the carrier."
Claim 50 recites a method of treating a long list of conditions including "anticoagulant disease", "diabetes", and "heart failure" by delivering these particles into the urinary bladder. Diabetes and heart failure are systemic metabolic and cardiovascular pathologies, not localized diseases of the urinary system. Treating systemic heart failure or diabetes via intravesical instillation lacks clinical clarity within the bounds of the steps in Claim 49.
In addition, the claim recites "anticoagulant disease" as an ailment. This term is not a recognized medical condition and is therefore unclear. An anti-coagulant is a class of pharmaceutical agents, not a disease or medical condition (unlike conditions such as a thromboembolic disorder or coagulopathy). One of ordinary skill in the art would not be reasonably certain about the scope of the claim (see Nautilus, Inc. v. Biosig Instruments, Inc., 572 U.S. 898, 910 (2014)). Thus, the overall scope of the method is ambiguous and indefinite to a person skilled in the art.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. § 102 and 103 (or as subject to pre-AIA 35 U.S.C. § 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. § 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, 6, 7, 8, 9, 28, 29, 48-58, 60 and 61 are rejected under 35 U.S.C. § 102(a)(1) as being anticipated by Kinsella et al. (US20210100950A1; published 08 April 2021, hereinafter “Kinsella”).
Kinsella describes a plurality of particles, each particle comprising an active substance and optionally a carrier substance (¶[0015] and ¶[0017]). The carrier substance corresponds to the excipient. Further Kinsella teaches wherein the particles have a buoyancy resulting in flotation in a urine contained in a bladder (¶[0015]) and density less than 1 kg/m³ (¶[0019]). The coating or structure may be designed to create a uniform or non-uniform rate of release (¶[0030]), wherein uniform release directly teaches a substantially constant rate. The active agent may be released upon exposure to liquid as described in ¶[0047] and ¶[0048].
Kinsella teaches wherein the configurations could be spheres or any other three-dimensional shape (¶[0031]) and the description of FIG. 3A recites, “the particles 110 can comprise micro-spheres or have any number of other shapes.” (¶[0051]). Kinsell teaches the carrier substance can comprise a degradable material (¶[0017] and claim 21), wherein the specification further teaches that the degradation within the bladder over time may occur (¶[0027] and ¶[0030]; biodegradation) and list suitable materials including biodegradable materials (¶[0030]).
Kinsella recites, “Therapeutic actions may include treatment, prevention, or diagnostic of many conditions or diseases including but not limited to urinary tract infections, bladder cancer, kidney cancer, ureter cancer, urethra cancer, anti-coagulant disease, diagnostic imaging, overactive bladder, underactive bladder, retained urine, diabetes, heart failure (fluid retention and or reduction), kidney failure and or supplementary treatments with dialysis, cystitis, and many other conditions.” (¶[0030]). In addition, Kinsella teaches many active agents including antibiotics (anti‑infective), anesthetics (lidocaine, bupivacaine), diuretics (furosemide, hydrochlorothiazide), anticoagulants, coagulants, chemotherapy (cisplatin, gemcitabine), contrast agents (gadolinium, barium), and agents for incontinence/overactive bladder are implicit from the listed indications (¶[0030]). Antibacterial agents are taught as antibiotics and silver sulfadiazine and anti‑infectives include anti‑fungal and antiviral agents (¶[0030]).
Kinsella teaches active agents can be embedded within a matrix of the carrier material whereby the matrix releases the agent (i.e., matrix with active agent dispersed therein; ¶[0061]). The active may be present as a coating that coats the carrier substance or located within the carrier substance (¶[0017], ¶[0030] and claim 24), teaching a coated particle system.
Kinsella claim 17 teaches intraurethral delivery of buoyant particles to treat a urinary disorder, anticipating the method of instant claim 48. The instant claim 49 method steps providing buoyant particles, delivering into bladder, wherein particles may degrade and be excreted over time, and release of active are described in ¶[0015], ¶[0021], ¶[0022], ¶[0027], ¶[0030] and ¶[0061] and claim 17 of Kinsella. The additional step of “allowing excretion and/or degradation” is a consequence of the method when using degradable particles, wherein degradation and discharge are taught. Thus, Kinsella fully teaches this method. The ailments of instant claim 50 are taught by Kinsella in ¶[0030] and urease inhibitor, chelating agent, antibacterial agent, and enzyme active agents are taught by Kinsella in ¶[0016] and claim 19.
Kinsella’s method of delivering the plurality of particles through the urethra teaches intraurethral delivery (claim 17, ¶[0021]). Kinsella projects retention at 30-90 days from the presented long‑term retention data (FIG. 5B) and describes devices that degrade/excrete over time (¶[0027]), thus teaching over about one month and greater than a one-month period. The disclosure of a uniform rate of release (¶[0030]) teaches a steady‑state release profile.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. § 102 and 103 (or as subject to pre-AIA 35 U.S.C. § 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 and 14 are rejected under 35 U.S.C. § 103 as being unpatentable over Kinsella et al. (US20210100950A1; published 08 April 2021, hereinafter “Kinsella”) in view of Palugan et al. (Intravesical drug delivery approaches for improved therapy of urinary bladder diseases. Int J Pharm X. 2021 Oct 23;3:100100; hereinafter “Palugan”).
Claim 1 is anticipated by Kinsella as discussed above, however Kinsella does not explicitly teach the limitations of instant claim 14, depending from claim 1.
Kinsella teaches where a size of each particle of the plurality of particles falls within a pre-determined size range (claim 17, ¶[0015], ¶[0021], ¶[0053]), and can employ any range of particle size (¶[0055]), including <400 micrometers (0.4 mm; ¶[0019], ¶[0055] and claim 30), however wherein the optimal particle size depends on the bladder size of the individual or animal being treated which will likely have a different optimal particle sizes and particle size would also be varied based on intended treatment (¶[0055] and ¶[0056]).
In ¶[0057] Kinsella reinforces that particles can be designed with different shapes or sizes, wherein methods of treatment may include delivering groups of differently sized particles. Kinsella recites, “The present disclosure can also include a method of delivering groups of differently sized particles and determining which size is best retained for treatment of an individual patient.” (¶[0023]) and wherein the size of the particles should allow for passage through the urethra to prevent blockage and avoid any increase in the frequency of urination (¶[0055] and ¶[0056]). Evidentiary reference, Ahmed et al. (Factors predicting the spontaneous passage of a ureteric calculus of ⩽10 mm. Arab J Urol. 2015 Jun;13(2):84-90. Epub 2014 Dec 6), reports kidney stone passage rates by size (see Abstract and Table 2), wherein choosing a mean diameter size of <10 mm, ideally less ≤ 5mm would be an obvious choice for one of skill in the art, to allow it to readily traverse the urethra and ≥2 mm to reduce the chance of accidental voiding.
Thus, the specification expressly contemplates varying the particle size to optimize retention depending on the patient and treatment goals. Moreover, the specification envisions particles as implants, that are buoyant bodies, and describes them as spheres, cubes, three-dimensional star shapes, etc., with no rigid upper size limit (¶[0031]).
Palugan teaches that is was known in the art at the time of the effective filing date of the instant invention that multiple spherical units having a diameter of 2.4 or 4 mm in an indwelling intravesical drug delivery system have been used to treat overactive bladder syndrome, whereby the multiple spherical units are inserted into the bladder through the urethra via a catheter to provide sustained bladder retention and prolonged release of a therapeutic drug, wherein the PLGA-PEG matrix biodegrades in a predictable manner and microspheres exit the bladder with minimal risk of potential obstruction and are eliminated in the urine. Thus, reducing the number of catheterization procedures (i.e., multiple intravesical instillations) and achieving sustained localized drug levels in the bladder for long time periods (page 5, section 5.2.1.1). Tailoring of drug release can further be fine-tuned by adjusting the particle dimensions and the number of particles for a specific therapeutic drug to meet the specific therapeutic goals of treatment.
Further, larger particles innately provide a greater volume to carry higher absolute amounts of active agent and excipient, wherein a formulation intended to deliver a drug throughout a drug delivery period of at least about one month, would require a particle size sufficient to contain a depot of drug sufficient to maintain therapeutic concentrations over that entire period without needing an impractically large number of smaller particles.
It is well understood that for matrix-type or coated particles, a larger size reduces the surface-area-to-volume ratio. This typically results in a more extended, near-zero-order release profile, which aligns with the substantially constant release rate. Larger sphere particles having a 2-8 mm mean diameter provides a much longer diffusional path and slower erosion rate compared to the <400 µm diameter particles highlighted in the rugae-retention embodiment exemplified by Kinsella, making it an obvious choice when a month-long steady release is desired.
Although the rugae fold entrapment mechanism taught by Kinsella depends on smaller size particles (<400 µm), the buoyancy mechanism causing particles to coat the surface of the bladder as it contracts taught by Kinsella does not, wherein a 2.5-4 mm buoyant particle will still float to the top of the urine and remain at the air-fluid interface as the bladder empties, minimizing contact with the urethral outlet until the very end of voiding. A particle size from 2-8 mm is large enough to be mechanically hindered from passing through the urethra, particularly when the bladder neck is closed or during the intermittent flow of urine. This provides an alternative or supplementary retention mode to the rugae entrapment, especially for patients whose rugae cleft dimensions vary.
In addition, larger particles that still including a mucoadhesive material would still provide a means to provide some amount of particle trapping in the rugae mucosal tissue folds of the interior walls of the bladder, upon bladder contraction that occurs with urine voiding. Accordingly, in addition to buoyancy, and mucoadhesion, a larger particle size, from that of the <400 µm particle embodiments highlighted in Kinsella, provide an enhanced mechanism to help ensure particle retention within the bladder for sustained release of the active agent throughout the extended drug delivery period.
In addition, larger 2-8 mm or 2.5-4 mm spherical particles are easier to fabricate uniformly by common techniques such as extrusion-spheronization, melt-congealing, or dripping into a hardening bath, compared to consistently producing large quantities of well-calibrated 100 µm range microspheres. A person of ordinary skill in the art would be motivated to select a size that balances performance with scalable, reproducible manufacturing.
Thus, it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to use a specific particle size have a mean diameter of about 2-8 mm or about 2.5-4 mm, as taught by Palugan (2.4- and 4-mm diameter particles), in the invention of Kinsella. A person of ordinary skill in the art would have been motivated to increase the sub-400 µm range particles taught by Kinsella to larger size 2-8 mm or 2.5-4 mm particles to achieve a longer retention/dwell time within the bladder to provide for sustained release of the active agent for an extended drug delivery period, as taught by Palugan, as a matter of routine, predictable optimization of the invention by Kinsella (see In re Woodruff, 919 F.2d at 1578 (Fed. Cir. 1990)).
The combined goals of long-term sustained release, high drug loading, simplified retention (via buoyancy and size exclusion), and the explicit suggestion to tailor particle size for individual retention taught by Kinsella would have provided ample motivation for a skilled artisan to formulate particles with a mean diameter of 2-8 mm or 2.5-4.0 mm, with a reasonable expectation of success based on the effective use of this size range for an intravesical drug delivery system taught by Palugan.
Kinsella itself contemplates a method of delivering groups of differently sized particles and determining which size is best retained for treatment of an individual patient. This is an explicit invitation to the skilled artisan to experiment with size ranges beyond the sub-400 µm example, including larger diameters, to achieve optimal retention and therapy duration. Hence, exploring a 2-8 mm or 2.5-4.0 mm size range is merely a routine, predictable optimization of a parameter that the prior art identifies as variable and outcome-determinative.
Claims 1, 17, 49 and 59 are rejected under 35 U.S.C. § 103 as being unpatentable over Kinsella et al. (US20210100950A1; published 08 April 2021, hereinafter “Kinsella”) in view of Schlievert and Peterson (US20180289656A1; published 11 October 2018, hereinafter “Schlievert”).
Claim 1 is anticipated by Kinsella as discussed above, however Kinsella does not explicitly teach the limitations of instant claim 17, depending from claim 1. In addition, the limitations of instant claim 49 are anticipated, as discussed above, however, Kinsella does not explicitly teach the limitations of instant claim 59, depending from claim 49.
Regarding instant claim 17, Kinsella does not recite specific weight percentages, but it teaches that the active agent can be present as a coating, embedded in a matrix, or contained within a cavity, with the carrier making up the balance (¶[0030] and ¶[0061]). Determining the appropriate drug loading to achieve buoyancy and sustained release is a routine formulation optimization within the capability of one of ordinary skill. Therefore, the broad ranges of instant claim 17 would have been obvious to optimize for a desired release profile. Furthermore, the teachings of Schlievert are discussed below, encompassing the limitations of instant claim 17.
Regarding instant claim 59, Kinsella mentions delivery by syringe (¶[0020] and claim 32) and catheter (¶[0022]), suggesting a fluid vehicle for delivery and stating that the buoyant particles can contain a liquid and that the material should be rapidly and effectively drained through a catheter and or introduced into the bladder through the same effective delivery vehicle or through a colloid or solution (¶[0031]. The use of a liquid vehicle to deliver particles via a catheter is standard practice.
In addition, Kinsella mentions that the particles can be suspended in a fluid for instillation (¶[0048] and ¶[0049]). Suitable material listed in ¶[0030] include several viscosity adjusting agents (polycaprolactone, chitosan, polyethylene glycol, poly lactic acid, poly lactic-co-glycolic acid, n′n-isopropylacrylamide, acrylamido taurate, polyethylene, polypropylene, collagen or gelatin gels, polyacrylamide gels, or glass; see also ¶[0031] polymers), buffers (hydrochloric acid, EDTA, and sodium hydroxide). Further, Kinsella describes an exemplary embodiment wherein the particles comprise silver sulfadiazine embedded within polylactic-co-glycolic acid or silver sulfadiazine coated glass microspheres (¶[0060]) and wherein the active agents can comprise coatings and/or can be embedded within a matrix of the carrier material, using agents such as one or more substances that control pH of the urine or decrease effective solutes for crystallization within the urine.
For example, the matrix can be coated with EDTA (¶[0061]). The addition of a tonicity-adjusting agent or buffer is a routine measure to render a liquid physiologically compatible and such modifications are well within the skill of an ordinary formulator. Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to incorporate a physiological liquid with a routine excipient (e.g., viscosity adjusting agent, dispersant, or buffer) to the invention of Kinsella because doing so is suggested by Kinsella (see KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007)) and is further supported by the teachings of Schlievert, as detailed below.
Schlievert teaches that it was known in the art at the time of the instant effective filing date that formulations for treating urinary system disorders (i.e., urinary tract infections; Abstract) can include about 10-100 mg/mL active compound with about 0.0001-0.05 M from the group consisting of lactic acid, ascorbic acid, citric acid, ethylenediaminetetraacetic acid, and combinations thereof (¶[0014]) with a topical solution comprising about 73.55 w/w % propylene glycol, about 25 w/w % polyethylene glycol 400 about 1.25 w/w % hydroxyethyl cellulose or hydroxypropyl cellulose, and about 1-25 w/w % saline and/or water and alternatively plant-derived oils including palm oil, olive oil, corn oil, and combinations thereof (¶[0016]).
Schlievert teaches example embodiments comprising 2.5%, 5%, 7.5%, and 10% active therapeutic agent (¶[0055]), falling within the instant claimed range (see MPEP § 2123). The active agent maybe selected from an antibacterial and anti-fungal or combinations thereof (claim 35) . In addition, Schlievert teaches the dose of active ingredients depends on the nature of the infection or illness, administration site, patient weight, age, sex, and surface area, concomitant medications, and medical judgment (¶[0081]). The active agent comprising ≤10% with very small molar amounts of an accelerant (0.0001-0.05 M; claim 1) leaves the excipient to make up the overwhelming bulk of the formulation, encompassing an about 5-97.5 wt. % excipient. Thus, the about 2.5-25 wt% active ingredient to about 5-97.5 wt% excipient limitation of instant claim 17 is encompassed within the teaching of Schlievert.
Schlievert further teaches in some embodiments, the formulation is applied in swab, or other material, and then applied to the skin or mucosal surface of the patient using the respective material. As used herein, the term “swab” refers to a material suitable for applying a liquid to a mucosal surface, or the act of applying a liquid, to the mucosal surface (¶[0074]). In other embodiments, the formulation is applied to or impregnated in a urinary catheter or other indwelling device ant the coated device is then placed in a patient using known processes and procedures (¶[0075]).
While Schlievert focuses on gel-based formulations that already contains a viscosity-adjusting agent (e.g., hydroxyethyl cellulose) for intravesical application, a liquid vehicle, such as water, saline, or a less-viscous polymer solution, is a well-known format for instillation into the bladder. A person of ordinary skill in the art reading this disclosure by Schlievert would understand that any physiologically compatible liquid carrier capable of being expelled through a catheter could be used. For decades, bladder instillations using liquids like saline, dimethyl sulfoxide, or heparin solutions have been standard medical practice. The choice between a gel and a liquid for this purpose is a design choice driven by the desired flow properties, not a change in function, wherein both serve to carry and disperse particles into the bladder via a catheter.
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to implement a predictable variation. Here, the Schlievert explicitly suggests that particles can be delivered through a catheter and could be instilled by injection (¶[0031]). Thus, it would be immediately apparent to a skilled artisan that a liquid vehicle is easier to inject through a small-diameter catheter than a viscous gel, providing a clear design incentive to use a less viscous carrier. The predictable result is that the particles would still disperse and float in the urine and the change from gel to liquid does not alter the particle buoyancy or release mechanism (see In re Aller, 220 F.2d 454, 456 (C.C.P.A. 1955)).
Moreover, instant claim 59 recites only a liquid vehicle with at least one of a viscosity adjusting agent, a tonicity adjusting agent, a buffer and a dispersant. This broad language encompasses countless conventional intravesical solutions. Both a gel and the liquid are inert carriers that temporarily suspend the buoyant particles during delivery, wherein the therapeutic particles themselves operate identically once inside the bladder. The buoyant particles operate by floating to the urine surface, wherein this mechanism does not depend on the viscosity of the delivery vehicle, thus using a liquid rather than a gel would not interfere with flotation.
The gel's only additional function, conferring viscosity, is not required by the claims, which merely require the presence of at least one of a viscosity-adjusting agent, a tonicity-adjusting agent, a buffer, or a dispersant. Because the prior art gel contains a viscosity adjuster, it anticipates a liquid vehicle. Even if treated as distinct, the substitution of a free-flowing liquid for a gel is an obvious modification that does no more than yield a predictable result (see KSR Int’l Co. v. Teleflex Inc., 550 U.S. 416 (2007)). One of ordinary skill in the art would have had a reasonable expectation that a liquid vehicle would successfully disperse the particles in the bladder, achieving the same therapeutic retention described in the prior art.
Claim 46 is rejected under 35 U.S.C. § 103 as being unpatentable over Kinsella et al. (US20210100950A1; published 08 April 2021, hereinafter “Kinsella”), in view of Palugan et al. (Intravesical drug delivery approaches for improved therapy of urinary bladder diseases. Int J Pharm X. 2021 Oct 23;3:100100; hereinafter “Palugan”), and in further view of Schlievert and Peterson (US20180289656A1; published 11 October 2018, hereinafter “Schlievert”), Ottoboni et al. (US20010019719A1; published 06 September 2001, hereinafter “Ottoboni”), and Terry (US20050064176A1; published 24 March 2005).
Regarding instant claim 46, the limitations of a controlled release pharmaceutical formulation for intravesicular administration to a subject to treat a bacterial infection of the bladder or urinary tract, wherein the particles are buoyant in urine and provide for sustained release of the active agent in the bladder throughout a drug delivery period of at least about one month, wherein the controlled release carrier comprises a mucoadhesive material to facilitate particle retention by the bladder wall are anticipated by Kinsella, as described above. The limitation of a population of particles having a mean diameter in the range of about 2.5-4.0 mm is taught by Palugan, as described above for instant claim 14. The limitation of wherein the particles comprise 50-95 wt. % of carrier is taught by Schlievert, as described above for instant claim 17.
Ottoboni claims 1 and 2 teaching a bioerodible, sustained-release preparation for placement into the bladder through the urethra comprising a pharmaceutically active ingredient and a bioerodible pharmaceutically acceptable carrier with said carrier being capable of sustained delivery within the bladder of said active ingredient and said carrier being excretable through the urinary tract after bioerosion, wherein said preparation has a specific gravity less than about 1.005 at 25° C.
Kinsella also teaches coatings or surface configurations to be retained (¶[0027]) that may include chitosan as a material used to construct the buoyant bodies (¶[0030]). Chitosan, is a well-known mucoadhesive polymer (see evidentiary reference Kolawole et al., Advances in intravesical drug delivery systems to treat bladder cancer. Int J Pharm. 2017 Oct 30;532(1):105-117, and see also MPEP 2144.04 regarding admission of known properties). Thus, a carrier comprising a mucoadhesive material is taught by Kinsella, wherein using a known mucoadhesive polymer (e.g., chitosan) would have been a routine modification with a reasonable expectation of success.
In addition, Kinsella teaches that therapeutic agents used in embodiments of the invention may comprise silver sulfadiazine (¶[0030]), a common topical anti-infective, dispersed in a carrier (¶[0060]), thus, incorporating it in a carrier matrix is obvious. Kinsella expressly identifies silver sulfadiazine as one of the contemplated therapeutic agents. Once silver sulfadiazine is selected from the finite list expressly taught by Kinsella, optimization of its loading within the carrier to achieve the desired sustained-release profile constitutes routine pharmaceutical formulation within the ordinary skill in the art. Kinsella however does not explicitly teach the use of 5-50 wt. % of silver sulfadiazine.
As discussed above, Schlievert teaches example embodiments comprising 5%, 7.5%, and 10% active therapeutic agent (¶[0055]), falling within the instant claimed range (see MPEP § 2123), with a very small molar amounts of an accelerant (0.0001-0.05 M; claim 1) leaving the excipient to make up the overwhelming bulk of the formulation, encompassing an about 50-97.5 wt. % excipient. The active agent maybe selected from an antibacterial and antifungal or combinations thereof (claim 35), wherein the anti-infective silver sulfadiazine taught by Kinsella.
In addition, Schlievert teaches the dose of active ingredients depends on the nature of the infection or illness, administration site, patient weight, age, sex, and surface area, concomitant medications, and medical judgment (¶[0081]). Increasing drug loading can increase payload, prolong release duration, reduce required particle number, reduce total polymer volume, help maintain therapeutic concentrations, and minimize repeated catheterization which are all predictable engineering adjustments.
Moreover, Terry teaches coating a medical device as a substrate (such a catheter ¶[0003]) with at least one type of antimicrobial particle dispersed within a polymeric base coat (claim 1; including mucoadhesive acrylic copolymers and block co-polymers as detailed in claim 3), wherein silver sulfadiazine may be selected for the antimicrobial particles (claim 4) and any concentration of the antimicrobial particles may be used in the base coat as long as there is sufficient polymer in the base coat to hold the particles in place, including antimicrobial particles at concentrations of <75 weight %, more preferably < 50 weight %, and most preferably between about 30-50 weight % (¶[0041]).
An objective of the invention is controlled of the release of the antimicrobial agent (¶[0017]). The Example 1 embodiment by Terry used 40% active silver particles in the base coat solution (remaining 60% balance; ¶[0046] and ¶[0047]). Thus, Terry demonstrates that polymer controlled-release antimicrobial systems conventionally employ antimicrobial loadings up to about 50 wt% dispersed within a carrier of >50 wt% is taught by Terry’s Example 1.
While Terry’s disclosure relates to an anchored coating of a medical device (e.g., a catheter) with a polymer base coat containing silver sulfadiazine particles, one of skill in the art would be motivated to apply a coating composition’s drug loading to a free‑floating, buoyant intravesical particle composition because the drug loading is dictated by the need for prolonged release, independent of the substrate, and both are polymeric controlled‑release carriers. Kinsella teaches the specific selection of silver sulfadiazine, wherein using 5-50 wt% is routine optimization based on the teachings of Terry (see In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003), regarding optimization of a result-effective variable, wherein drug loading is unquestionably a formulation variable).
Thus, it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to combination of these known elements to arrive at the invention of instant claim 46. Kinsella expressly identifies silver sulfadiazine as one of a finite number of suitable anti-infective agents for incorporation into the disclosed buoyant intravesical delivery particles. Terry demonstrates that controlled-release polymer systems conventionally employ antimicrobial loadings approaching 30-50 wt.% while maintaining structural integrity and controlled release. Drug loading is a recognized result-effective formulation variable affecting payload, release duration, and release kinetics. Accordingly, once silver sulfadiazine is selected from the finite class expressly identified by Kinsella, determining an appropriate loading between about 5 wt.% and 50 wt.% would have constituted no more than routine optimization through ordinary experimentation, with a reasonable expectation of success (see In re Aller, 220 F.2d 454, 456 (CCPA 1955) and In re Peterson, 315 F.3d 1325, 1329-30 (Fed. Cir. 2003)).
A person of ordinary skill in the art would have been motivated to modify Kinsella’s buoyant, sustained-release system to treat bladder infections more effectively by incorporating a mucoadhesive polymer to enhance particle retention on the bladder wall, selecting silver sulfadiazine (taught by Kinsella), a proven anti‑infective for urinary tract infections, using known effective loading concentrations taught by Terry. The prior art recognizes the problems of drug washout during voiding and the need for prolonged local antimicrobial levels (Kinsella ¶[0006]; see also evidentiary reference Kolawole et al., 2017). Combining a buoyant particle with a mucoadhesive carrier and a long-acting anti‑infective is a straightforward solution that uses each element for its known purpose to yield a predictable result of greater retention and sustained silver sulfadiazine release (see KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007), wherein combining familiar elements according to known methods is obvious when it yields predictable results). No new function arises from the combination, each component merely performs the same task it did in the individual references.
A person of ordinary skill in the art would have had a high expectation of success because Kinsella already demonstrated that floating particles can achieve month‑long constant release in urine. Terry demonstrated that mucoadhesive carriers can be loaded with drug particles at up to 50 wt% and retain the drug for controlled release. No unexpected results or formulation incompatibilities would have been anticipated. Thus, the claimed formulation is a predictable assembly of known components (i.e., floating particle, mucoadhesive polymer, and silver sulfadiazine at known loadings), each performing its known function to achieve the expected result of prolonged intravesical anti‑infective therapy.
Claim Rejections – Nonstatutory 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).
Claims 1, 2, 6-9, 14, 17, 28, 29, and 48-61 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, 8-11, 17, 24, 26, 27, 35, 36, 38, and 40 of co-pending US Application No. 18/285,645 (published as US20240189237A1; hereinafter “’645”). Although the claims at issue are not identical, they are not patentably distinct from each other because each limitation of the instant claims is either expressly recited in the claims of the ’645 application or represents an obvious variation of the subject matter claimed therein, as detailed below. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented (see MPEP § 804.03).
Instant claim 1 claims an intravesical drug delivery system comprising buoyant particles with an excipient portion and an active agent, wherein the active agent is released at a substantially constant release rate. The co-pending ’645 application claim 1 recites an intravesical controlled release formulation comprising a population of microparticles with a controlled release carrier and a pharmacologically active agent, wherein the microparticles are buoyant in urine. Claim 26 (which depends from claim 24, which depends from claim 5) recites that the controlled release carrier provides “approximately zero order release.” A substantially constant release rate is equivalent to zero-order release. It would have been obvious to combine the buoyant particles of ’645 claim 1 with the zero-order release profile of ’645 claim 26, yielding the system of instant claim 1. Therefore, claim 1 is not patentably distinct.
Regarding instant claim 2 (particles are substantially spherically or cylindrically shaped) the ’645 application claims do not expressly recite a shape, however microparticles for intravesical delivery are routinely formed as microspheres (i.e., spherical). A spherical shape is a conventional, predictable design choice that does not render the claim patentably distinct over the ’645 claims.
Regarding instant claim 6 (excipient portion is comprised of a degradable material), the ’645 application claim 10 recites that the carrier “gradually dissolves, degrades, or erodes in urine to release the pharmacologically active agent.” This is exactly a degradable excipient, thus, there is no patentable distinction.
Regarding instant claim 7 (active agent is a drug for the treatment of a disorder of the urinary system), the entire ’645 disclosure and specifically claim 35 are directed to treating a urinary system disorder by intravesical administration. The active agent in the ’645 claims is inherently a drug for such a disorder, thus, there is no patentable distinction.
Regarding instant claim 8 (active agent is one or more of an anti-infective, anesthetic, analgesic, diuretic, anti-inflammatory, coagulant/anticoagulant, chemotherapeutic, incontinence agent, RAAS inhibitor, kidney stone agent, or contrast agent), claim 17 of the ’645 application recites the identical list of pharmacologically active agents. No patentable distinction.
Regarding instant claim 9 (anti-infective agent is an antibacterial, antifungal, or antiviral), the ’645 claim 17 anti-infective agents broadly encompass antibacterial, antifungal, and antiviral agents thus, there is no patentable distinction.
Regarding instant claim 14 (particles have a mean diameter of about 2-8 mm or sub-ranges), the ’645 application claim 1 recites a mean diameter of 500 nm to 2000 μm (i.e., 0.5 μm to 2.0 mm). The instant range begins at about 2.0 mm, overlapping at the boundary, and extends to 8.0 mm. It was well known in the art at the relevant time that larger millimeter-sized floating beads (e.g., 2.74 mm) were used for intravesical drug delivery to enhance retention and drug loading (see evidentiary reference Palugan et al., Intravesical drug delivery approaches for improved therapy of urinary bladder diseases. Int J Pharm X. 2021 Oct 23;3:100100). Enlarging the ’645 microparticles to the 2-8 mm range to achieve longer retention or higher payload is a routine optimization of a degree of size and would have been obvious (see In re Woodruff, 919 F.2d at 1578 (Fed. Cir. 1990), wherein a change in size is a difference in degree that is prima facie obvious absent unexpected results). Thus, instant claim 14 is not patentably distinct.
Regarding instant claim 17 (particles comprise about 2.5 wt.% to about 25 wt.% active agent and about 5 wt.% to about 97.5 wt.% excipient), the ’645 application claim 1 recites 2.5 wt.% to 95 wt.% active agent and 5 wt.% to 97.5 wt.% carrier. The instant narrower range of active agent is entirely within the ’645 range. Selecting a specific sub-range from a known broad range is an obvious design choice absent a showing of criticality, thus, no patentable distinction is present.
Regarding instant claim 28 (particles comprise a matrix with the active agent dispersed therein), the ’645 application claim 8 directly recites the carrier is comprised of a matrix and the pharmacologically active agent is dispersed therein thus, no patentable distinction is present.
Regarding instant claim 29 (particles comprise a coating on a core with the active agent dispersed therein), the ’645 application claim 9 directly recites “the carrier comprises a coating on a core that comprises the pharmacologically active agent dispersed therein.” Thus, there is no patentable distinction.
Regarding instant claim 46 (controlled release formulation with particles of 2.5-4.0 mm, specific gravity <1.005, comprising 50-95 wt.% mucoadhesive controlled release carrier and 5-50 wt.% silver sulfadiazine, providing sustained release ≥1 month), the size is an obvious variation as described for instant claim 14 above. The ’645 claim 2 recites a mean specific gravity of less than 1.03. A specific gravity of <1.005 is a predictable sub-set that enhances buoyancy, and therefore, it is an obvious optimization.
The ’645 claim 11 recites a carrier that may comprise a fatty acid, fatty alcohol, fatty acid ester, phospholipid, sterol, polyethylene glycol alkyl ether, polyoxyethylene-polyoxypropylene block copolymer, or chitosan. Chitosan, which is a well-known mucoadhesive polymer (see evidentiary reference Kolawole et al., Advances in intravesical drug delivery systems to treat bladder cancer. Int J Pharm. 2017 Oct 30;532(1):105-117, and see also MPEP 2144.04 regarding admission of known properties). In addition, the instant specification details suitable mucoadhesive materials (¶[0180]) which are encompassed within the carrier materials recited in ’645 claim 11. Therefore, a carrier comprising a mucoadhesive material is taught by the ’645 claims.
The ’645 claim 17 recites an anti-infective agent, silver sulfadiazine is a common topical anti-infective and is further specifically named in the ’645 specification (¶[0015]). Kinsella expressly identifies silver sulfadiazine as one of the contemplated therapeutic agents. Once silver sulfadiazine is selected from the finite list expressly taught by Kinsella, optimization of its loading within the carrier to achieve the desired sustained-release profile constitutes routine pharmaceutical formulation within the ordinary skill in the art. Further, ’645 claim 24 recites a drug delivery period of 2 hours to six months, encompassing one month. Thus, a one-month release is expressly disclosed. The combination of these known elements would have been obvious to one of ordinary skill, thus instant claim 46 is not patentably distinct.
Regarding instant claim 48 (method of treating a urinary system ailment comprising intraurethral administration of the particles), the ’645 application claim 35 recites a method of treating a urinary system disorder by intravesical administration of buoyant microparticles. The use of the particles of instant claim 1, which are an obvious variation as shown above, in the same method is not patentably distinct. Intraurethral administration is inherent in intravesical instillation via a catheter.
Regarding instant claim 49 (method of treating/preventing an ailment comprising providing buoyant particles, delivering them into the bladder, allowing excretion/degradation over a period, wherein particles comprise excipient and active agent that is released), the ’645 application claim 35, in light of the specification, describes the same method of providing buoyant microparticles (excipient/carrier + active), delivering them intravesically (via catheter through urethra), with the drug being released over time as the carrier degrades (claim 10) and residual carrier gradually eliminated. The recited steps are either identical or inherently present. No patentable distinction is present.
Regarding instant claim 50 (ailment list such as, UTI, bladder cancer, kidney cancer, etc.), the ’645 application claim 40 recites the urinary system disorder is infection, cancer, incontinence, kidney stone, or UTI. The instant list is a mere expansion that is obvious in view of the known intravesical treatments.
Regarding instant claim 51 (active agent is a urease inhibitor, chelating agent, antibacterial agent, or enzyme), these agents fall within the broad categories of the ’645 application claim 17, particularly the anti-infective and kidney stone agents. The selection is an obvious choice with no patentable distinction.
Regarding instant claim 52 (excipient portion is degradable), this is obvious over ’645 claim 10, as described for instant claim 6 above. Regarding instant claim 53 (active agent for urinary system disorder), the same rationale applies as described for instant claim 7 above. Regarding instant claim 54 (active agent list), the same rationale applies as described for instant claim 8 above. Regarding instant claim 55 (delivering particles intraurethrally). Intravesical administration inherently involves passage through the urethra, thus, this step is implicit in the ’645 method and no patentable distinction is present.
Regarding instant claim 56 (period of time is more than one month), ’645 claim 24 recites a drug delivery period up to six months, thereby teaching a >1-month period. Regarding instant claim 57 (particles are a matrix with dispersed active), the same rationale applies as described for instant claim 28 above. Regarding instant claim 58 (coating on a core), the same rationale applies as described for instant claim 29 above.
Regarding instant claim 59 (particles dispersed in a liquid vehicle comprising at least one of a viscosity adjusting agent, tonicity adjusting agent, buffer, and dispersant), the ’645 application claim 27 expressly recites a liquid vehicle in which the population of microparticles is dispersed, the liquid vehicle comprised of a viscosity adjusting agent, a tonicity adjusting agent, a buffer, and a dispersant. The instant claim requires only at least one of these components, which is a subset. Therefore, no patentable distinction is present.
Regarding instant claim 60 (active agent released over about one month), as noted for instant claim 56, the ’645 application teaches a 2-hour to 6-month release period, thus, one month is within that range and is an obvious design goal for extended therapy. Therefore, no patentable distinction is present. Regarding instant claim 61 (active agent released at a substantially steady state), ’645 claim 26 teaches approximately zero order release, which is a substantially steady state release, and thus, it is obvious with no patentable distinction.
In summary, all instant claims define inventions that are either explicitly claimed or obvious variations of the inventions claimed in the ’645 application. Because the two applications are co-pending and commonly owned (or share a common inventor), and no terminal disclaimer has been filed, a provisional nonstatutory obviousness-type double patenting rejection is entered.
This rejection is provisional and will be maintained until the conflicting ’645 application issues as a patent or is abandoned. If the ’645 application becomes a patent, the rejection may be converted to a non-provisional rejection. The applicant may overcome this rejection by filing a terminal disclaimer in compliance with 37 C.F.R. § 1.321 once the conflicting application matures into a patent, or by establishing that the claims are patentably distinct through amendment or argument.
Claims 1, 2, 6-9, 14, 17, 28, 29, and 48-61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of US Patent No. 11,241,538 B2 (hereinafter “’538”). Although the claims at issue are not identical, they are not patentably distinct from each for the reasons outlined below.
The ’538 patent, and particularly claim 1 thereof, is directed to a method of improving retention of particles in the urinary bladder. The method comprises providing buoyant particles having a therapeutic substance and a pre-determined size range, and delivering them through the urethra so that they are retained by the rugae during bladder contraction. The specification of the ’538 patent further describes that the particles may include a carrier substance, degradable materials, specific active agents, and that the active agent can be released over time. (col. 3, lines 11-30 and col. 4, line 53-col. 5, line 42) The instant claims are directed to an intravesical drug delivery system, a controlled release formulation, and methods of treatment, all of which are obvious variations of the invention claimed in the ’538 patent.
More specifically, instant claim 1 claims an intravesical drug delivery system comprising buoyant particles with an excipient portion and an active agent, wherein the active agent is released at a substantially constant release rate. The ’538 patent claim 1 recites a method that uses particles having buoyancy and that include a therapeutic substance (i.e., active agent). The patent specification explicitly teaches that the particles can include a carrier substance (excipient) and that the carrier substance may be a degradable material or polymer (col. 3, lines 11-30 and col. 4, line 53-col. 5, line 42). The specification further teaches that the release rate can be designed to be “a uniform … rate of release” (col. 4, lines 58-63), which is a substantially constant release rate.
It would have been obvious to one of ordinary skill to configure the buoyant therapeutic particles of the ’538 method into a drug delivery system that delivers the active agent at a constant rate, as taught by the ’538 specification itself. Therefore, claim 1 is not patentably distinct from the invention claimed in the ’538 patent.
Regarding instant claim 2 (particles are substantially spherically shaped), the ’538 patent specification describes the particles as “spheres” (col. 5, lines 44-47) and refers to “micro-spheres” (col.8, lines 15-17). A spherical shape is an obvious choice that would have been apparent to one of ordinary skill in forming particles for the system of claim 1.
Regarding instant claims 6 and 52 (excipient portion is comprised of a degradable material), the ’538 patent teaches that the carrier substance (excipient) can comprise a degradable material (col. 3, lines 16-17) and specifically identifies degradable polymers and other materials that break down in the bladder (col.4, lines 35-38). The use of a degradable excipient is explicitly taught by the patent and is not patentably distinct.
Regarding instant claims 7 and 53 (active agent is a drug for the treatment of a disorder of the urinary system), the ’538 patent is directed to treating and/or preventing urinary tract infections and other urinary system disorders, and it describes delivering therapeutic agents directly to the bladder (col.3, lines 7-10). The active agent in the ’538 method inherently treats a urinary system disorder, thus, there is no patentable distinction.
Regarding instant claims 8 and 54 (active agent is one or more of an anti-infective, anesthetic, analgesic, diuretic, anti-inflammatory, coagulant/anticoagulant, chemotherapeutic, incontinence agent, RAAS inhibitor, kidney stone agent, or contrast agent), the ’538 patent specification lists exactly these classes of agents antibiotics, silver, silver ions, anesthetic agents, lidocaine, bupivacaine, chemotherapy agents, cisplatin, gemcitabine, loop diuretics, anti-fibrinolytic compounds, anticoagulant compounds, coagulant compounds, contrast agents, and overactive bladder agents (col.4, line 53-col. 5, line 26). The claimed list is substantially identical to the disclosure, and its incorporation into the claimed system would have been obvious.
Regarding instant claim 9 (anti-infective is an antibacterial, antifungal, or antiviral), the ’538 patent lists antibacterial agents (antibiotics, silver) and notes anti-infective properties col.4, line 53-col. 5, line 26). Selection of any specific anti-infective is an obvious choice from the known class.
Regarding instant claim 14 (particles have a mean diameter of about 2-8 mm, or sub-ranges), the ’538 patent claim 13 recites a pre-determined size range of less than 400 micrometers, which is the exemplified range for rugae entrapment. However, the patent specification expressly contemplates varying the particle size to optimize retention and notes that the size can depend on the patient (col. 9, lines 13-39). Moreover, the specification envisions particles as implants that are buoyant bodies and describes them as spheres, cubes, three-dimensional star shapes with no rigid upper size limit (col. 5, lines 43-47). At the time of invention, it was well known that larger millimeter-sized floating beads (e.g., 2.74 mm) were used for intravesical drug delivery to enhance drug loading and retention (see evidentiary reference Palugan et al., Intravesical drug delivery approaches for improved therapy of urinary bladder diseases. Int J Pharm X. 2021 Oct 23;3:100100). Enlarging the particles from sub-400 µm to the 2-8 mm range to achieve a longer dwell time or different retention mechanism is a routine, predictable optimization and therefore not patentably distinct (see In re Woodruff, 919 F.2d at 1578 (Fed. Cir. 1990)).
Regarding instant claim 17 (particles comprise about 2.5 wt.% to about 25 wt.% active agent and about 5 wt.% to about 97.5 wt.% excipient), the ’538 patent does not recite specific weight percentages, but it teaches that the active agent can be present as a coating, embedded in a matrix, or contained within a cavity, with the carrier making up the balance (col. 10, lines 19-41). Determining the appropriate drug loading to achieve buoyancy and sustained release is a routine formulation optimization within the capability of one of ordinary skill. Therefore, the recited ranges are not patentably distinct.
Regarding instant claims 28 and 57 (particles comprise a matrix with the active agent dispersed therein), the ’538 patent explicitly teaches that the active agents can be embedded within a matrix of the carrier material (col. 12, lines 21-22). This limitation is taught and obvious.
Regarding instant claims 29 and 58 (particles comprise a coating on a core with active agent dispersed therein), the ’538 patent teaches that the therapeutic agent may be present as a coating and that the coating may cover a core containing the agent (col. 12, lines 23-24). The configuration of a coating over a drug-dispersed core is an obvious variation directly suggested by the patent.
Regarding instant claim 46 (a controlled release pharmaceutical formulation for treating a bacterial infection, comprising buoyant particles of mean diameter 2.5-4.0 mm, specific gravity <1.005, with 50-95 wt.% mucoadhesive carrier, and 5-50 wt.% silver sulfadiazine dispersed within, providing sustained release at least one month), the ’538 patent claims and specification provide the foundation for this formulation. The patent teaches buoyancy (density less than urine), a size range that can be optimized up to the millimeter scale as explained above, the use of an anti-infective agent (silver sulfadiazine is listed in col. 5, line 8), and release over an extended period. The patent discusses carrier materials that can provide controlled release and notes that the device can be indwelling in order to maintain a controlled release therapeutic effect over a period of time (col.4, lines 30-35) and projects retention at 30-90 days (FIG. 5B). The addition of a mucoadhesive material to enhance retention is an obvious design expedient for an intravesical system where retention is the primary objective, wherein the patent itself suggests coatings or surface configurations which would enable the device to be retained (col. 4, lines 35-43). Using a known mucoadhesive polymer (e.g., chitosan) would have been a routine modification with a reasonable expectation of success. Thus, claim 46 is not patentably distinct.
Regarding instant claim 48 (a method of treating an ailment comprising intraurethral administration of the particles), the ’538 patent claims a method of improving retention that uses buoyant therapeutic particles delivered intraurethrally to treat conditions (e.g., UTI). The method of claim 48 merely recites the therapeutic purpose inherent in the ’538 method. It is an obvious use of the same system.
Regarding instant claim 49 (method of treating/preventing an ailment comprising providing buoyant particles, delivering them into the bladder, and allowing excretion/degradation over a period of time, wherein the particles comprise an excipient and an active agent that is released), the ’538 patent claim 1 recites providing buoyant particles, delivering them through the urethra, and the particles being retained over multiple filling/emptying cycles. The patent teaches that the particles may degrade and be excreted (col. 4, lines 35-38) and that they release therapeutic agents (col.4, line 53-col. 5, line 26). The additional step of allowing excretion and/or degradation is an inherent consequence of the method when using degradable particles; thus, the claimed method is essentially the same as, or obvious from, the ’538 method.
Regarding instant claim 50 (ailment is a urinary tract infection, bladder cancer, etc.), the ’538 patent lists these exact ailments, urinary tract infections, bladder cancer, kidney cancer, ureter cancer, urethra cancer, anti-coagulant disease, overactive bladder, underactive bladder, retained urine, diabetes, heart failure, kidney failure, and cystitis (col. 5, lines 34-42). This limitation is directly taught.
Regarding instant claim 51 (active agent is a urease inhibitor, chelating agent, antibacterial agent, or enzyme), the ’538 patent recites that the therapeutic substance can be a urease inhibitor, a chelating agent, an antibacterial agent, an enzyme, and a combination thereof (col. 10, lines 26-33). This limitation is identical to the patent’s teaching.
Regarding instant claim 55 (delivering the particles comprises intraurethral delivery), the ’538 patent method requires delivering the plurality of particles through a urethra (claim 1). This is identical.
Regarding instant claims 56 and 60 (period of time/release period is more than one month/about one month), the ’538 patent describes retention over 30 days and projects retention at 30, 60, and 90 days (FIG. 5B). Release over a one-month period is an obvious design goal for an extended-release intravesical system.
Regarding instant claim 59 (particles dispersed in a liquid vehicle containing at least one of a viscosity adjusting agent, tonicity adjusting agent, buffer, and dispersant), the ’538 patent does not explicitly recite a liquid vehicle in its claims, but it describes delivering the particles using a syringe (claim 15) and mentions that the particles can be delivered in a capsule or coating that dissolves, or that they can be suspended in a fluid for instillation (col. 7, lines 31-42). The use of a liquid vehicle to deliver particles via a catheter is standard practice and the ’538 specification notes that a fluid can be present in the bladder to assist delivery (col.7, lines 1-3). Incorporating a physiological liquid with routine excipients (e.g., saline, buffer, a dispersant) would have been obvious to one of ordinary skill and does not render the claim patentably distinct (see KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007)).
Regarding instant claim 61 (active agent released at a substantially steady state), the ’538 patent teaches that the release rate can be a uniform rate of release (col. 4, lines 60-63). A steady state release profile is the same as a uniform rate and is therefore obvious.
In summary, all of the instant claims merely recite embodiments that are either explicitly described in the ’538 patent or are obvious, predictable variations of the invention claimed in the ’538 patent. The scope of the instant claims would extend the period of exclusivity beyond the term of the ’538 patent for the same inventive concept. Therefore, the instant claims are unpatentable under the doctrine of nonstatutory obviousness-type double patenting.
This rejection may be overcome by filing a terminal disclaimer under 37 C.F.R. § 1.321 that disclaims the terminal portion of any patent granted on the instant application beyond the full statutory term of the ’538 patent, provided the requirements of common ownership or a common inventor are met and the disclaimer is accompanied by the required fee. Alternatively, applicant may amend or argue to show that the claims are patentably distinct.
Conclusion
No claims are allowed.
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/RL Scotland/
Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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