DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-25 were previously pending.
By virtue of a Preliminary Amendment, filed 18 October 2024, Applicant amended claims 1-7, 9, 11, 14, 16, and 18-24 and cancelled claims 8, 10, 15, 17, and 25.
Therefore, claims 1-7, 9, 11-14, 16, and 18-24 are now pending and currently under examination.
Priority
Acknowledgment is made for the following priority:
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Information Disclosure Statement (IDS)
The information disclosure statement filed 18 October 2024 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered.
Specifically, there is no corresponding Non-Patent Literature document to the IDS entry cited as Kim et al. “Comparative Physiochemical and Pharmacokinetic Properties of Quetiapine and Its Active Metabolite Norquetiapine.”
Applicant is reminded of their duty to disclose to the Office all information known to the person to be material to patentability as defined in 37 CFR 1.56. As stated therein, “[e]ach individual associated with the filing and prosecution of a patent application has a duty of candor and good faith in dealing with the Office, which includes a duty to disclose to the Office all information known to that individual to be material to patentability as defined in this section.”
Claim Objections
Claims 4, 20, and 21 are objected to because of the following informalities:
Claim 4 recites, “[t]he solution claim 1…” The deletion of ‘of’ is assumed to be a typographical error. Appropriate correction is required.
Claim 20 recites a pH range of 6,8. This is assumed to be a typographical error and appropriate correction is required.
Claim 21 recites, “[a] method of preventing, treating or ameliorating at least one symptom of delirium in a subject the method comprising administering…” A comma should be placed between ‘subject’ and ‘the.’
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 the applicant regards as his invention.
Claims 1, 3, 6, 11-14, 16, and 18 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 (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites, “[a]n aqueous solution consisting essentially of water, a quetiapine salt, and either or both of a benzoic acid salt and a citric acid salt….” The partially open transitional phrase ‘consisting essentially of’ permits additional, unrecited ingredients only when those ingredients do not materially affect the basic and novel characteristics of the claimed composition. See MPEP 2111.03(III). Although ‘consisting essentially of’ is a recognized transitional phrase, the scope of the present claims is unclear because the specification and claims do not provide an objective basis for determining:
What properties constitute the basic and novel characteristics of the claimed composition;
What degree of change in those properties constitutes a material effect; and
Which additional ingredients, and at what concentrations, are permitted or excluded.
The potentially relevant basic and novel characteristics appear to include maintaining a quetiapine salt in a dissolved aqueous state at pH 5-7 and providing a formulation suitable for pharmaceutical/intravenous administration. However, the claims do not define which of these characteristics control the scope of ‘consisting essentially of’ or determining when an additional ingredient materially affects such characteristics.
This uncertainty is further apparent from dependent claims 11-14, 16, and 18, which depend from and include all the limitations of claim 1, and add ingredients capable of materially affecting the properties of the claimed solution in instant claim 1:
Claim 11 adds one or more of an amino acid, a glycol, and a pharmaceutically acceptable organic acid. Such ingredients have the ability to function as pH modifiers, buffers, solvents, solubilizers, stabilizers, viscosity modifiers, or tonicity agents;
Claims 12 and 13 recite amino acids, particularly L-arginine in claim 13. L-arginine has the ability to modify pH, ionic strength, precipitation behavior, stability, and osmolality;
Claim 14 recites organic acids such as benzoic acid, citric acid, and lactic acid. These organic acids have the ability to modify pH, buffering capacity, salt formation, ionization, solubility, and precipitation of the solution;
Claim 16 recites glycols which have the ability to function as cosolvents, solubilizers, viscosity modifiers, or stabilizers and may materially affect quetiapine solubility and stability;
Claim 18 broadly recites pharmaceutically acceptable carriers, diluents, or excipients. This broad genus encompasses ingredients such as preservatives, antibacterial or antifungal agents, isotonic agents, absorption-delaying agents, surfactants, and cosolvents, some of which may materially affect the claimed solution.
The additional ingredients recited in claims 11-14, 16, and 18 are permitted only to the extent they do not materially affect the basic and novel characteristics of the solution recited in claim 1. However, the claims and specification do not provide an objective standard for distinguishing permitted amounts and uses of those ingredients from amounts and uses that would be excluded by the ‘consisting essentially of’ limitation.
Accordingly, a person of ordinary skill in the art (‘POSITA’) would not be able to determine, with reasonable certainty, the metes and bounds of claims 1, 11-14, 16, and 18.
Applicant may overcome the rejection by amending the claims to identify the relevant basic and novel characteristics and provide objective limits for determining material effect, by specifically identifying the permitted additional ingredients and amounts, or by replacing ‘consisting essentially of’ with a transition that more accurately reflects the intended claim scope.
Claim 3 is rejected under 35 U.S.C. 112(b) for the following reason:
Claim 3 recites that “the concentration of the quetiapine salt is at least about 0.1 mg/ml to about 5 mg/ml.” The phrase ‘at least about 0.1 mg/ml to about 5 mg/ml’ renders the scope of the claimed concentration unclear. The term ‘at least about’ ordinarily indicates an open-ended concentration having a lower boundary of approximately 0.1 mg/ml and greater, with no recited upper boundary. In contrast, the phrase ‘to about 5 mg/ml’ ordinarily indicates that approximately 5 mg/ml is the upper endpoint of a closed concentration range. Therefore, a POSITA would not be able to determine the metes and bounds of the claim with reasonable certainty. For purposes of claim interpretation, claim 3 will be read as “wherein the concentration of the quetiapine salt is about 0.1 mg/ml to about 5 mg/ml.”
Claim 6 is rejected under 35 U.S.C. 112(b) for the following reason:
Claim 6, which depends from claim 1, recites, “…wherein the quetiapine is not conjugated to an amino acid or fatty acid.” There is lack of antecedent basis for this limitation in claim 6 because claim 1 recites quetiapine salt, not quetiapine.
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 21-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating or ameliorating at least one symptom of delirium, does not reasonably provide enablement for preventing a symptom of delirium.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)).
These include:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based
on the content of the disclosure
All of the Wands factors have been considered with regard to the instant claims as discussed below:
(A)/(B) The breadth of the claims/The nature of the invention:
The claims are directed to a method of preventing, treating, or ameliorating at least one symptom of delirium in a subject, the method by administering a therapeutically effective amount of an aqueous solution comprising water, a quetiapine salt, and either or both of a benzoic acid salt and a citric acid salt at pH 5-7.
The specification defines ‘subject’ as including any human or non-human animal including, but not limited to, dogs, cats, horses, cows, sheep, and pigs ([0036]). The specification defines ‘therapeutically effective amount’ as an amount of an agent sufficient to produce a desired therapeutic or pharmacological effect in the subject being treated, requiring a POSITA determine the effective dose ([0034]). The specification provides a broad dosing schedule of:
A daily intravenous dose of about 0.01 mg/kg to about 100 mg/kg body weight in one or multiple doses per day ([0071]); and
A concentration of quetiapine from 10 mg/day to about 50 mg/day ([0072]).
The specification does not provide parameters for what would constitute preventing delirium symptoms in a human or non-human subject, but preventing is interpreted as reducing the likelihood that delirium will occur, delaying its onset, or avoiding its occurrence in a subject who does not yet have delirium. This preventive use is distinct from treating or ameliorating delirium after its onset.
The claimed invention is a method of preventing a complex neuropsychiatric condition by prophylactically administering a pharmaceutical composition. Delirium is a clinically heterogenous syndrome having more than one cause or predictable course. Delirium may arise in association with critical illness, surgery, infection, metabolic disturbance, medication, withdrawal, organ dysfunction, neurological injury, sleep disruption, pain, or a combination of these factors.
Preventing a multifactorial syndrome such as delirium involves identifying at-risk subjects, intervening at an appropriate time, selecting a therapeutically effective and safe dose, and addressing causes that may differ substantially among patients. Preventing a syndrome is substantially different from treating a symptom after the syndrome has already manifested.
The nature of the invention therefore requires meaningful empirical evidence and specific clinical guidance.
(C)/(E) The state of the prior art/The level of predictability in the art:
At the relevant filing date, quetiapine was known as an effective agent in the treatment of both the positive (hallucinations, delusions) and negative symptoms (emotional withdrawal, apathy) of psychosis.1 A 2018 study suggested low dose prophylactic quetiapine use to prevent delirium in critically ill ICU patients.2 Within 72 hours of ICU admission, a total of 35 patients were randomly assigned to receive either placebo or one dose of oral quetiapine (12.5 or 25 mg) per day for 10 days or until ICU discharge if less than 10 days. The incidence of delirium in the quetiapine prophylactic group was 7 out of 15 subjects and 11 out of 20 subjects in the control group., which did not show a statistically significant reduction in the primary incidence endpoint (p=0.442). However, it did show significantly fewer CAM-ICU assessments and short delirium duration. This extremely small study with a very select group of subjects does not cover the full scope of prevention over the full scope of subjects in claim 21. Even Kim admits a further large prospective study is needed.
The Specification further acknowledges quetiapine has been used in the treatment of delirium in ICU patients ([006]). This background does not establish that quetiapine was known to reliably prevent delirium across the patient populations encompassed by claim 21. The Specification distinguishes pharmacological management of existing delirium from non-pharmacological prevention strategies. For example, the Specification identifies environmental modification and improved sleep, including use of earplugs, as interventions associated with delirium prevention ([081]). The disclosure therefore demonstrates that prevention and treatment were recognized as separate clinical problems and does not establish that therapeutic efficacy against existing delirium would have allowed one skilled in the art to predict prophylactic efficacy.
In addition, clinical prevention of delirium is biologically and clinically unpredictable. The occurrence of delirium is multifactorial, and an intervention capable of reducing agitation or treating symptoms once delirium has developed does not necessarily prevent the underlying syndrome from occurring in the first place.
Furthermore, the Specification acknowledges substantial patient-to-patient variability. For example, Applicant explains that the amount of quetiapine and dosage regimen depends on numerous variables including age, weight, gender, medical condition of the subject, severity of the disease, the route and frequency of administration, the particular compound employed, as well as the pharmacokinetic properties (e.g., adsorption, distribution, metabolism, excretion) of the individual treated, and states that the dosage “may vary widely” ([071]). The Specification further recognizes the dosage regimen may need to be optimized for each individual ([071]).
Such individualized variability is particularly significant in the context of prophylactic treatment because the skilled artisan must determine a dose and treatment schedule that will prevent a future clinical event from occurring. The complexity of doing so extends far beyond the scope of determining a safe and effective or symptom-reducing dose after the disease is present.
Neither the Specification nor the prior art provides an established relationship between quetiapine dose, plasma concentration, timing of administration, and probability of preventing delirium. Therefore, the field lacks the predictability necessary to extrapolate from the disclosed treatment concepts to the full prophylactic scope of claim 21 without substantial experimentation.
(F)/(G) The amount of direction provided by the inventor/The existence of working examples:
The amount of direction or guidance regarding prevention is limited and weighs strongly against enablement. The specification provides considerably more direction concerning treatment of existing delirium. The disclosure specifically states the dose of quetiapine for the treatment of delirium in an ICU patient, but fails to denote the prophylactic dose ([072]).
The Specification does not teach: how long before the anticipated delirium risk should quetiapine be administered; whether administration must begin before ICU admission, immediately upon admission, before surgery, after surgery, before a medically-triggering event, etc.; whether prophylactic administration should be continuous or intermittent; what does is effective for prevention; what plasma concentration correlates with prevention; how long prophylaxis treatment should continue; which subjects are sufficiently at risk to warrant prophylaxis; whether the prophylactic regiment differs for hypoactive, hyperactive, or mixed delirium; whether prophylactic effectiveness varies depending upon the etiology of delirium; or what magnitude of reduction in occurrence constitutes “preventing” delirium.
The Specification contains formulation studies directed to obtaining aqueous quetiapine solutions ([089]). These examples demonstrate the preparation and physical properties of the claimed pharmaceutical solutions, but do not demonstrate administration of the claimed aqueous quetiapine solution prevents delirium in a subject. In fact, there are no working examples describing a clinical study, randomized drug trial, animal model, or any other experimental evidence establishing prophylactic efficacy. There is likewise no disclosed example identifying: a prophylactic patient population; prophylactic quetiapine dose; timing of administration relative to delirium risk; duration of prophylaxis; or any statistically or clinically meaningful reduction in delirium occurrence attributable to the claimed solution.
The Specification instead discusses treatment or management of delirium and describes non-pharmacological interventions such as environment modification in connection with delirium prevention.
The absence of a working prevention example is not, itself, dispositive. However, when considered together with the breadth of the claims, unpredictability of delirium prevention, and lack of prophylactic dosing guidance, the absence of working examples materially supports the conclusion that the full scope of the prevention method is not enabled.
(D)/(H) The level of one of ordinary skill/The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
The level of ordinary skill in the art is relatively high. A person of ordinary skill would likely include a physician or clinical pharmacologist having knowledge concerning quetiapine pharmacology and management of hospitalized or critically ill patients.
A high level of ordinary skill does not cure the absence of teachings regarding which patients should receive preventative treatment, when such treatment should begin and at what dose, how long the treatment should last, and whether the claimed intervention will actually prevent delirium. The skilled artisan’s knowledge could permit routine administration of quetiapine, but would not substitute for the vast experimentation necessary to establish quetiapine prophylaxis across the breadth of subjects encompassed by the claims.
The amount and nature of experimentation required to practice the full preventative scope would be substantial and undue. A skilled artisan would be required to establish: patient populations who would respond to prophylactic quetiapine; which delirium etiologies are susceptible to prevention by quetiapine; appropriate criteria for identifying high-risk patients susceptible to delirium; the optimal time to initiate treatment; an effective prophylactic dose; dose-response relationships; appropriate intravenous or subcutaneous exposure; treatment frequency; duration of therapy; whether loading or maintenance doses are required; effects of concomitant ICU medications; safety and tolerability of administering quetiapine to patients who do not yet have delirium; and whether the selected regimen actually reduces the incidence of delirium relative to an appropriate control population. Determination of these parameters would not involve routine formulation optimization. It would require clinical investigation involving administration of quetiapine to populations of at-risk human subjects and comparison of subsequent delirium incidence under different dosing, timing, and treatment conditions.
Considering the evidence as a whole, the aforementioned Wands factors establish the specification does not enable one of ordinary skill to practice the full scope of the claimed prevention method without undue experimentation.
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, 4-7, 9, 11, 14, 16, and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Pliva (WO 2006/056771 A1, published 01 June 2006) in further view of Sudhakar (US 2021/0322440 A1, published 21 October 2021).
Regarding claim 1 –
Pliva teaches a liquid solution comprising pharmaceutically acceptable salts of quetiapine and expressly teaches the quetiapine salt is dissolved or dispersed, optionally with the addition of non-toxic anionic, cationic or non-ionic surfactants, and inorganic or organic buffers (p. 6, lines 28-31; p. 7, lines 1-2). Pliva further emphasizes the pharmaceutical formulations suitable for injection or infusion may be in the form of a sterile, aqueous solution that contains the quetiapine salt (p. 5, lines 19-24). Finally, Pliva identifies citric acid and sodium citrate as suitable pharmaceutically acceptable buffer components (p. 5, lines 14-16).
While Pliva does not expressly disclose the aqueous solution has a pH of 5 to 7, this limitation is made obvious by Sudhakar.
Sudhakar teaches an aqueous liquid pharmaceutical composition comprising quetiapine fumerate, which is a quetiapine salt; sodium benzoate, which is a benzoic acid salt; and purified water ([0003]). Sudhakar specifically exemplifies an oral liquid suspension formulation containing 28.83 mg/ml quetiapine fumerate, 0.3 mg/ml sodium benzoate, and 787.046 purified water ([0005]). Sudhakar further expressly teaches embodiments having a pH of 5-6.5, which falls within the presently claimed pH range of 5-7. See MPEP 2144.05.
Regarding claim 2 –
Sudhakar expressly teaches an aqueous quetiapine formulation containing quetiapine fumerate at a concentration of 28.83 mg/ml ([0005]). This amount falls within the claimed open-ended range of “at least 0.1 mg/ml.”
Regarding claims 4 and 5 –
Sudhakar expressly teaches quetiapine fumerate ([0005]).
Regarding claim 6 –
Both Pliva and Sudhakar use ordinary quetiapine salts, not quetiapine covalently conjugated to an amino acid or fatty acid. For example, a fumerate salt is not an amino acid or fatty acid conjugate as the fumerate is associated with pronated quetiapine as a salt, not covalently attached as a prodrug conjugate. Therefore, the references necessarily satisfy the limitations of claim 6.
Regarding claim 7 –
Sudhakar expressly teaches sodium benzoate ([0005]).
Regarding claim 9 –
Pliva expressly teaches sodium citrate (p. 5, lines 14-16).
Regarding claims 11 and 16 –
Pliva expressly teaches liquid polyethylene glycol as suitable for use in the intravenous quetiapine formulation (p. 5, lines 19-24). Pliva also expressly teaches citric acid as a suitable organic acid (p. 5, lines 14-16).
Regarding claim 14 –
Pliva expressly teaches citric acid buffer for use in the liquid quetiapine formulation (p. 5, lines 14-16).
Regarding claim 18 –
Pliva expressly teaches conventional pharmaceutical carriers and excipients (p. 4, lines 1-5).
Regarding claim 19 –
Pliva expressly teaches intravenous administration of the formulation (p. 3, lines 20-24).
Regarding claim 20 –
Sudhakar’s express pH range of 5 to 6.5 encompasses 6.1, 6.2, 6.3, 6.4, and 6.5 of the currently claimed list of alternative values.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to adjust the citrate-buffered aqueous quetiapine solution of Pliva to the mildly acidic pH range taught by Sudhakar, including a pH between 5-6.5. Both references concern pharmaceutical liquid formulations of the same active pharmaceutical ingredient, quetiapine, and Sudhakar expressly teaches that a pH within this range is suitable for aqueous quetiapine formulations. Once of ordinary skill would therefore have had a reason to employ Sudhakar’s known pH conditions when formulating Pliva’s aqueous quetiapine solution in order to provide suitable solubility, stability, and pharmaceutical acceptability.
Such modifications would have involved the application of known formulation conditions for quetiapine to another known aqueous quetiapine formulation and would have produced the predictable result of an aqueous quetiapine salt solution maintained within a pH range known to be suitable for quetiapine.
Accordingly, the aqueous solution of claims 1, 2, 4-7, 9, 11, 14, 16, and 18-20 would have been obvious over Pliva in view of Sudhakar.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Pliva (WO 2006/056771 A1, published 01 June 2006) and Sudhakar (US 2021/0322440 A1, published 21 October 2021) as applied to claims 1, 2, 4-7, 9, 11, 14, 16, and 18-20 above, and further in view of Tierney (US 9,993,486 B1, patent date 12 June 2018).
Pliva in view of Sudhakar renders obvious the aqueous quetiapine solution of claim 1 for the reasons set forth above. Claim 3 further requires the concentration of the quetiapine salt be from about 0.1 mg/ml to about 5 mg/ml and this limitation is made obvious in further view of Tierney.
As previously discussed, Sudhakar teaches that concentration of quetiapine fumerate in an aqueous liquid pharmaceutical composition is a formulation parameter and exemplifies quetiapine fumerate at concentrations greater than 0.1 mg/ml. Sudhakar does not expressly disclose a quetiapine concentration within the presently claimed range, but this limitation is made obvious in further view of Tierney.
Tierney teaches a quetiapine fumerate composition for oral administration (abstract). Specifically, Tierney teaches that quetiapine fumerate possesses moderate, pH-dependent aqueous solubility and reports solubility ranging from 94.3 mg/ml to 2.37 mg/ml at pH values from 1 to 9 (col. 7, lines 53-64). Tierney further explains that quetiapine fumerate solubility rapidly decreases with increasing pH and recognizes soluble liquid formulations as an alternative pharmaceutical dosage form (col. 7, lines 59-67, Fig. 5).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, when preparing the aqueous quetiapine solution taught by Pliva under the quetiapine formulation conditions taught by Sudhakar, to select a quetiapine fumerate concentration within its known aqueous solubility range as taught by Tierney. This would involve selecting a lower concentration of quetiapine fumerate with increasing pH because Tierney expressly teaches pH is a recognized result-effective variable for quetiapine fumerate solubility as shown in Figure 5 below:
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(col. 7, lines 59-61).
Accordingly, a person of ordinary skill would have also understood pH as a result-effective variable of quetiapine solubility and would have been motivated to optimize pH and drug concentration to obtain a stable aqueous solution in dissolved form rather than suspension. One of ordinary skill would have a reasonable expectation of success because Tierney expressly reports quetiapine fumerate aqueous solubility sufficient to accommodate concentrations falling within the claimed range.
Claims 12 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Pliva (WO 2006/056771 A1, published 01 June 2006) and Sudhakar (US 2021/0322440 A1, published 21 October 2021) as applied to claims 1, 2, 4-7, 9, 11, 14, 16, and 18-20 above, and further in view of Pavliv (US 2004/0132823 A1, published 08 July 2004).
Pliva in view of Sudhakar renders obvious the aqueous quetiapine solution of claim 1 for the reasons set forth above. Claims 12 and 13 further require the solution comprises an amino acid and this limitation is made obvious in further view of Pavliv.
Pavliv teaches aqueous pharmaceutical solutions comprising a poorly water-soluble organic pharmaceutical active ingredient, together with L-arginine, and teaches that such compositions may be administered by intravenous or intramuscular injection ([0012], [0018], claim 6). Pavliv further teaches aqueous ibuprofen/arginine solutions having a pharmaceutically suitable pH below about 7.8 ([0015]).
The related injectable ibuprofen art further establishes that arginine was recognized as a solubilizing agent for maintaining poorly soluble organic pharmaceutical compounds in aqueous solution.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to include L-arginine in the aqueous quetiapine solution of Pliva/Sudhakar because the artisan was faced with the same general formulation problem addressed by Pavliv: maintaining an organic pharmaceutical active ingredient in a pharmaceutically acceptable aqueous injectable solution.
The skilled artisan would have been motivated to employ arginine because it was known to function as a pharmaceutically acceptable amino acid solubilizing agent in aqueous injectable formulations. Use of arginine in the quetiapine solution would have therefore represented application of a known pharmaceutical excipient for its known solubilizing function with a reasonable expectation of obtaining the predictable result of improved aqueous solubilization. One of ordinary skill would have had a reasonable expectation of success because Pavliv demonstrates actual preparation and parenteral administration of aqueous drug + arginine solutions and further expressly identifies arginine’s role in promoting aqueous solubility.
Accordingly, inclusion of an amino acid encompassed by claims 12 and 13 would have been obvious.
Claims 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over Pliva (WO 2006/056771 A1, published 01 June 2006) and Sudhakar (US 2021/0322440 A1, published 21 October 2021) as applied to claims 1, 2, 4-7, 9, 11, 14, 16, and 18-20 above, and further in view of Devlin (“Efficacy and safety of quetiapine in critically ill patients with delirium: A prospective, multicenter, randomized, double-blind, placebo-controlled pilot study,” published 2010).
Pliva in view of Sudhakar renders obvious the aqueous quetiapine solution of claim 1 for the reasons set forth above. Claims 21-24 further require a method of treatment by administering the aqueous quetiapine solution of claim 1 and this limitation is made obvious in further view of Devlin.
Regarding claims 21 and 23 –
Devlin teaches administration of quetiapine to critically ill adult ICU patients suffering from delirium (abstract). In Devlin’s study, quetiapine was administered at 50 mg every 12 hours, with dose escalation as necessary (p. 419). Devlin reports that quetiapine treatment significantly shortened the time to first resolution of delirium and reduced the duration of delirium compared with placebo (p. 421-422). Devlin expressly teaches administering a therapeutically effective amount of quetiapine for treating or ameliorating delirium (p. 421).
Regarding claim 22 –
Devlin expressly teaches agitation as a characterization of delirium in the treatment (p. 423, Table 3).
Regarding claim 24 –
Pliva expressly teaches that quetiapine salt formulations may be administered intravenously by infusion or injection. Although Devlin administered quetiapine orally, it would have been obvious to administer the quetiapine treatment intravenously using the sterile aqueous formulation expressly taught by Pliva.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to administer the aqueous quetiapine composition rendered obvious by Pliva and Sudhakar to a subject suffering from delirium because Devlin expressly teaches the same active pharmaceutical ingredient, quetiapine, is useful for treatment of delirium. One of ordinary skill would have been motivated to employ the aqueous dosage form taught by Pliva and Sudhakar in the method of Devlin because Pliva expressly teaches quetiapine salts as sterile aqueous formulations suitable for injection or infusion, thereby providing a known alternative means for systemically delivering the same pharmacologically active quetiapine moiety.
One of ordinary skill would have had a reasonable expectation of therapeutic success because changing the dosage form or route of administration would not change the identity of the active quetiapine compound.
Accordingly, the method of claims 21-24 would have been obvious over Pliva and Sudhakar in further view of Devlin.
Conclusion
Claims 4 and 20-21 are objected. Claims 1-7, 9, 11-14, 16, and 18-24 are rejected. No claim is allowed.
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Julia A. Rossi whose telephone number is (571)272-0138. The examiner can normally be reached M-Th 7:30-5:30 (MST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert A. Wax can be reached at (571)272-0623. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JULIA A. ROSSI/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
1 Kim (2003). “Treatment of Delirium in Older Adults with Quetiapine.”
2 Kim (2018). “Efficacy of Low Dose Prophylactic Quetiapine on Delirium Prevention in Critically Ill Patients: A Prospective, Randomized, Double-Blind, Placebo-Controlled Study.”
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