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 .
Priority
The instant application 18/508,992 filed on November 14, 2023 claims priority to, and the benefits of U.S. Provisional Application No. 63/383,547 filed on November 14, 2022.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on June 15, 2026, wherein claims 1, 3, 5, 7, 9, 11, 13, 15, 16 and 20 are amended; claims 17-19 are unchanged; claims 2, 4, 6, 8, 10, 12 and 14 are canceled; and claims 21-23 are newly added. Specifically, applicant added the new limitation that recites “175 ± 17.5 mg/mL sorbitol”, which is the narrower statement of the limitation “the sorbitol is present in 357 ± 35.7 mg/mL” in claim 6; and that changes the scope of the claims, and necessitates a new ground of rejection(s).
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 3, 5, 7, 9, 11, 13 and 15-23 are pending and under examination.
Action Summary
Applicant’s amendment to the claims overcome each and every objection previously sets forth in the Non-Final Office Action mailed on March 13, 2026.
Claim 16 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention are withdrawn in view of the claim amendment that specifically deletes the term “substantially”.
Claims 1-19 rejected under 35 U.S.C. 103 as being unpatentable over Calisti et al. (WO 2021058810 A1), in view of Rowe et al. (Pharmaceutical Press, 6th Edition: pp. 61-63, 242-244, 441-445, 627-629, 679-682), Marchetti et al. (WO 2009016069 A2), Meeks (Medical News Today, 2021: 1-3), FDA Staff (FDA.gov, 2010: 2-4), and Sharma et al (Ancient Science of Life, 1998. Vol. VIII(1): 39) are withdrawn in view of the claim amendments.
Claims 1-5, 8-9, and 14-20 rejected under 35 U.S.C. 103 as being unpatentable over Marchetti et al. (WO 2009016069 A2), in view of Promises Behavioral Health Editorial Team (Promises Behavioral Health, 2012: 2), Rowe et al. (Pharmaceutical Press, 6th Edition, pp. 242-244), FDA Staff (FDA.gov, 2010: 2-4), and Sharma et al (Ancient Science of Life, 1988. Vol. VIII(1): 39) are withdrawn in view of the claim amendments.
Claim Interpretation
The claimed term “oral solution”, when reasonably construed in view of the special definition provides in paragraph [0023] of the specification, is taken to includes oral liquid dosage form in which the active ingredient is mixed with a liquid, while being dissolved and/or dispersed therein. The active
ingredient particles are substantially dissolved and/or dispersed in the liquid.
Regarding the recitation of “solvent consisting of water” followed by the phrase of “[a]n oral solution comprising” in claim 21, the transitional term “comprising” recites in the preamble of the claim is inclusive or open-ended and does not exclude additional, unrecited elements; and therefore, given its broadest reasonable interpretation, while the claim recites “solvent consisting of water”, the transitional “consisting” followed after “solvent” only limits one solvent to be water, and does not further limit the oral solution as a whole to exclude additional, unrecited solvent.
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, 3, 5, 7, 9, 11, 13 and 15-19 are rejected under 35 U.S.C. 103 as being unpatentable over Calisti et al. (WO 2021/058810 A1; cited in the prior Office Action), in view of Marchetti et al. (US 10,292,931 B2), Harris et al. (US 2012/0022094 A1), Chen et al. (WO 2007/067331 A1) and Levenson et al. (US 2007/0178123 A1) (newly applied as necessitated by amendment).
Calisti et al. teaches trazodone is an antidepressant with combined serotoninergic receptor antagonism and serotonin reputable inhibition that give rise to its potential use in a broad range of co-morbidities of major depressive disorder (see e.g., p. 1, line10-17); and it is indicated primarily for the treatment of depression in patients who do not respond to antidepressants, such as selective serotonin reuptake inhibitors (see e.g., p. 1, line 10-13). Calisti et al. teaches sweeter formulations of trazodone are needed due to trazodone’s bitter taste (see e.g., p. 6, line 18-19). Calisti et al. further teaches multiple pharmaceutical suitable for oral administration to the pediatric population (see e.g., p. 1, line 5-8; p. 15, line 5-7), including exemplary oral drop solutions containing 15 mg/mL (1.5% w/v) or 30 mg/mL (1.5 w/v) of trazodone HCl (see e.g., p. 16, line 3-7), and syrup compositions with pH value of about 4.5, such as syrup “Trial C” shown below (see e.g., Table 8; p. 22, line 1):
PNG
media_image1.png
484
312
media_image1.png
Greyscale
.
Calisti et al. further teaches “EDTA” is an abbreviation for disodium edetate (see e.g., Table 7).
Please note the weight-by-volume percentage, wherein 1% (w/v) means 1 gram of solute per 100 mL of solution, can be convert to mg/mL using the equation of:
m
g
m
L
=
%
(
w
/
v
)
×
10
; and by employing the unit conversion, the Trial C syrup of Calisti et al. comprising 2.6 mg/mL of trazodone hydrochloride, 0.56 mg/mL of citric acid, 100 mg/mL of sorbitol, 1.3 mg/mL of methylparaben, and 0.5 mg/mL of disodium edetate (EDTA). Calisti et al. further teaches the syrup compositions do preferably comprise a preserving agent which is preferably selected in the group comprising methyl and propyl parahydroxybenzoate, potassium sorbate and mixture thereof; and the preferred is potassium sorbate or, alternatively, sodium benzoate (see e.g., p. 12, line 17-23). Calisti et al. further teaches alternatively, syrup composition have a trazodone concentration of 0.1 to 0.9 mg% (w/v) (see e.g., p. 11, line 16-21). Calisti et al. further teaches the dosage forms can also contain other traditional ingredients such as: preservatives, stabilizers, surfactants, buffers, salts for regulating osmotic pressure, emulsifiers, sweeteners, colorants, flavourings and the like, suitable for pediatric use (see e.g., p. 15, line 15-18). Calisti et al. further teaches the invention is suitable for use in the treatment of insomnia in the pediatric population (see e.g., abstract).
Although Calisti et al. teaches the incorporation of sodium benzoate as the preserving agent to the syrup compositions, the prior art does not expressly teach 1.0 ± 0.1 mg/mL of sodium benzoate. Although Calisti et al. teaches other traditional ingredients, such as stabilizers, sweeteners, colorants, flavourings and the like can also contain therein, and teaches an exemplary syrup composition Trial C comprising: 2.6 mg/mL of trazodone hydrochloride, 0.56 mg/mL of citric acid, 100 mg/mL of sorbitol, 1.3 mg/mL of methylparaben, and 0.5 mg/mL of disodium edetate (EDTA) (see calculation above), the prior art also does not expressly teach the claimed amount of trazodone hydrochloride, citric acid, sorbitol and methylparaben; and does not does not expressly teach 3.0 ± 0.3 mg/mL of edetate disodium dihydrate, 1.5 ± 0.15 mg/mL of sodium saccharin, FD & C Red No. 40, and cherry flavor.
Marchetti et al. teaches trazodone alleviates the characteristic symptoms of depression (see e.g., Col. 1, line 29-30), and is preferably used medically in the form of a pharmaceutically acceptable salt of acid addition, and more preferably in the form of the hydrochloride (see e.g., Col. 1, line 49-51). Marchetti et al. further teaches various liquid formulations, for oral use (drops, syrup) or parenteral use (vials for injection), with concentrations of trazodone hydrochloride equal to approx. 1 % (w/v), are being marketed; However, low concentration of trazodone involve counting a large number of drops to give the therapeutic dosage (see e.g., Col. 2, line 14-21 and 24-26). Marchetti et al. further teaches there is still a great need for a liquid pharmaceutical composition of trazodone hydrochloride for oral administration in which an amount of trazodone hydrochloride greater than or equal to 1 % (w/v) can be dissolved stably, does not contain ethanol as solvent or cosolvent, and does not turn yellow over time (see e.g., Col. 2, line 37-42). Marchetti et al. further teaches the solubility of trazodone hydrochloride in the presence of mixtures of cosolvents can reach concentration levels of the order of 10-15% (see e.g., Col.3, line 9-11); preferably, the liquid pharmaceutical composition comprises two cosolvents, each independently in an amount in the range from 5% to 50% (w/v) (see e.g., Col. 3, line 16-20); and at leave two solvent selected from the group glycols and polyglycols makes it possible to obtain a stable liquid composition (see e.g., Col. 7, line 4-8). Marchetti et al. further teaches the concentration of trazodone hydrochloride in the liquid pharmaceutical composition is preferably between 1 % and 15% (w/v) (see e.g., Col. 2, line 64-67). Marchetti et al. further teaches in water, the solubility of trazodone hydrochloride increases with increase in acidity of the aqueous medium (see e.g., Col. 1, line 66-67).
Harris et al. teaches storage-stable syrup formulations, which contains only components recognized as being safe for human ingestion (see e.g., [0006]), including exemplary syrup formulation in Example 1 suitable for pediatric use shown below (see e.g., Example 1; [0024]; [0015]):
PNG
media_image2.png
513
370
media_image2.png
Greyscale
.
Harris et al. further teaches preferred buffering system includes citric acid buffer system and those capable of maintaining a pH in the range of greater than about 4.5; preferably there is about 0.1 to about 10 grams/liter of sodium citrate, and about 0.05 to about 5 grams/liter of citric acid (see e.g., [0016]); which gives about 0.05 mL/mL to about 5 mg/mL of citric acid. Harris et al. further teaches suitable pharmaceutically acceptable solvents and/or carrier system include water, alcohols and glycols, especially, inter alia, propylene glycol, sorbitol and/or polyethylene glycol; use of a combination of at least one of water, propylene glycol, sorbitol and glycerin is preferred; sortibol may be present in a concentration of about 100 to 250 mg/mL (see e.g., [0015]). Harris et al. further teaches the term "percent" is used herein it is intended to represent percent by weight (see e.g., [0009]). Harris et al. further teaches suitable non-sugar based artificial sweetening agents for use in the present invention include saccharin; and the sweetening agent may be present in amounts such as, for instance, about 0.01 % to about 10% (see e.g., [0014]). Harris et al. further teaches sugar based syrup formulations it is often desirable to employ antimicrobial preservatives; the amount of a pharmaceutically acceptable preservative required to protect a syrup against microbial growth varies with the proportion of water available for growth, the nature and inherent preservative activity of some formulative materials and the capability of the preservative itself; among the preservatives commonly used in the preservation of syrups with the usually effective concentrations are benzoic acid (0.1 to 0.2%), sodium benzoate (0.1 to 0.2%), and various combinations of methyl-, propyl-, and butylparabens (totaling about 0.1 %)(see e.g., [0018]). Harris et al. further teaches stabilizers may also be incorporated into the syrup formulation and in amounts of about 0.01 to about 5%; useful aminopolycarboxylic acids and salts thereof are those which are safe for ingestion and have sufficient solubility in the syrup formulations to make a stable single phase composition; and the alkali metal salts of ethylenediaminetetraacetic acid (“EDTA”) are preferred (see e.g., [0019]). Harris et al. further teaches most syrups are flavored with synthetic flavorants or with naturally occurring materials; and typical flavoring agents which are commonly used in sweetened pharmaceuticals, foods, candies, beverages are also useful in the present invention, including cherry and bubble gum (see e.g., [0021]). Harris et al. further teaches the antihistaminic syrup formulations of the present invention may also contain one or more other drugs for obtaining more than one therapeutic result from a single dose (see e.g., [0011]).
Chen et al. teaches the pharmaceutical formulations, including liquid dosage form such as oral syrup (see e.g., [0001]), containing at least one stabilizer to help improve the stability of d-penicillamine when in a liquid dosage form; and the preferred stabilizer is disodium EDTA or disodium dihydrate EDTA (see e.g., [0061]). Chen et al. further teaches artificial sweeteners may be include, but are not limited to saccharin, and the preferred artificial sweeteners are, inter alia, sodium saccharin (see e.g., [0057]), and sodium saccharin is a soluble saccharin salt from and water-soluble (see e.g., Table I, “Water-soluble Artificial Sweeteners”).
Levenson et al. teaches comestible products containing medicaments such as dextromethorphan may have a bitter or unpleasant off-note taste that adversely affects the overall flavor of the product (see e.g., [0003]); and coloring can be used in amounts effective to produce a desired color for the comestible; and suitable colors include, inter alia, FD&C red #40 (see e.g., [0055]).
Although the prior arts do not expressly disclose each and every ingredient in the claimed mg/mL, converting between concentration format (e.g., from w/v to mg/mL; or from w/w to mg/mL) or determine the corresponding mg/mL concentration based on the density of the formulation would have been routine mathematical conversion within the ordinary skill of a pharmaceutical formulator. The prior art discloses the identity and relative amounts of the formulation components, and a person of ordinary skill in the art would have routinely determined the corresponding mg/mL concentration when preparing or optimizing the formulation. Therefore, expressing the composition in terms of mg/mL would have been an obvious matter or routine optimization and does not patentably distinguish the
claimed composition. The weight-by-volume percentage(s), wherein 1% (w/v) means 1 gram of solute per 100 mL of solution, can be convert to mg/mL using the equation of
m
g
m
L
=
%
(
w
/
v
)
×
10
, for example, 0.26 w/v % of trazodone hydrochloride, which when calculated by
0.26
g
100
m
L
×
1000
m
g
1
g
=
2.6
m
g
/
m
L
, gives 2.6 mg/mL of trazodone hydrochloride. The weight-by-weight percentage(s), wherein 1% (w/w) means 1 gram of solute per 100 g of solution, can convert to mg/mL using the density of the solution, for example, 0.1 to 0.2 w/w% of sodium benzoate in the formulation, and the formulation has a density of 1 g/mL, which when calculated by:
0.1
g
100
g
×
1
g
1
m
L
×
1000
m
g
1
g
=
1
m
g
/
m
L
0.2
g
100
g
×
1
g
1
m
L
×
1000
m
g
1
g
=
2
m
g
/
m
L
, gives 1-2 mg/mL of sodium benzoate.
The difference between the syrup composition Trial C of Calisti et al. (2.6 mg/mL of trazodone hydrochloride, 0.56 mg/mL of citric acid, 100 mg/mL of sorbitol, 1.3 mg/mL of methylparaben, and 0.5 mg/mL of disodium edetate; a pH value of 4.5) and the claimed invention is that prior art does not expressly teach the claimed amount of trazodone hydrochloride, citric acid, sorbitol, methylparaben; and does not expressly teach the incorporation of 1.0 ± 0.1 mg/mL of sodium benzoate, 3.0 ± 0.3 mg/mL of edetate disodium dihydrate, 1.5 ± 0.15 mg/mL of sodium saccharin, FD & C Red No. 40, and cherry flavor. However, Marchetti et al. teaches there is a need for liquid formulations with an amount of trazodone hydrochloride greater than or equal to 1 % w/v, which is greater or equal to 10 mg/mL, that can achieve therapeutic dosage with fewer drops/smaller volume, and teaches the use of at least two cosolvents can obtained a stable liquid composition of trazodone hydrochloride at concentration between 1% and 15% (w/v), which gives 10 mg/mL to 150 mg/mL of trazodone hydrochloride. Harris et al. teaches storage-stable oral syrup formulations comprising a combination of pharmaceutically acceptable solvents, including formulations comprising citric acid, sorbitol, saccharin, edetate disodium, saccharin, flavoring agents (such as cherry or bubble gum), and water; and further teaches 0.1 to 0.2 w/w% of sodium benzoate (about 1 mg/mL to about 2 mg/mL of sodium benzoate), and various combinations of methyl-, propyl-, and butylparabens (totaling about 0.1 w/w %; which is about 1 mg/mL) are antimicrobial preservatives that can be added to protect syrup from microbial growth; and teaches the workable range for the ingredients, including about 0.05 mL/mL to about 5 mg/mL of citric acid as the buffering system to adjust pH; about 100 to 250 mg/mL of sorbitol as one of the pharmaceutically acceptable solvents; about 0.01 w/w % to about 10 w/w % (which is about 0.1 mg/mL to about 100 mg/mL) of non-sugar based artificial sweetening agent, such saccharin; and about 0.01 w/w % to about 5 w/w% (about 0.1 mg/mL to about 50 mg/mL) of stabilizer, such as alkali metal salts of EDTA/edetate disodium. Chen et al. teaches disodium dihydrate EDTA is a preferred alternated stabilizer on a par with disodium EDTA, and sodium saccharin is a preferred artificial sweeteners and a water-soluble salt form of saccharin. Levenson et al. teaches FD&C red #40 is a suitable colors to produce a desired color for the comestible containing bitter medicaments. In view of the foregoing, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by 1) modifying the oral syrup composition Trial C of Calisti et al. in view of the oral syrup formulation taught by Harris et al., by adding a sweetener (such as saccharin), another antimicrobial preservative (sodium benzoate), and a flavoring agent, 2) substituting one art recognized pharmaceutically acceptable excipient with another of the same function as taught by Harris et al. and Chen et al., by substituting bubble gum flavor with cherry flavor as taught by Harris et al., substituting EDTA (edetate disodium) with disodium dihydrate EDTA (edetate disodium dihydrate), and saccharin with sodium saccharin as taught by Chen et al. 3) adding a known coloring agent FD&C red #40 to produce a desired color for bitter medicaments as taught by Levenson et al., and 4) optimizing the concentration of each and every pharmaceutically acceptable excipient based upon its function and the workable range taught by Harris et al. through routine optimization in order to arrive at a stable oral syrup composition comprising trazodone hydrochloride at a concentration of 10 mg/mL to 150 mg/mL that can achieve therapeutic dosage with fewer drops/smaller volume as taught by Marchetti et al. One would have been motivated to do so, because Marchetti et al. teaches the solubility of trazodone hydrochloride in the presence of mixtures of cosolvent can reach a concentration between 1% and 15% (w/v), which is 10 to 150 mg/mL of trazodone hydrochloride; and Harris et al. teaches an oral syrup that can contain one or more drugs other than desloratadine, comprising more than one pharmaceutically acceptable solvents (including sorbitol and water), citric acid, sweetening agent (saccharin), antimicrobial preservatives (including sodium benzoate, and methylparaben), stabilizer (edetate sodium) and flavoring agent (including cherry) and teaches that the concentrations of these pharmaceutically acceptable excipients are result-effective-variable during the preparation of oral syrup, because different concentration produce different physical or chemical properties, e.g., changing the concentration of artificial sweetening agent changes the sweetness level; Chen et al. teaches interchanging disodium EDTA with disodium dihydrate EDTA as stabilizer, and sodium saccharin with saccharin as artificial sweetener is well-known and routine in the art; and Levenson et al. teaches adding coloring agent, such as FD&C red #40, is routine technique for producing a desired color for bitter medicaments. Accordingly, modifying the oral syrup composition by interchanging one art recognized pharmaceutically acceptable excipient with another of the same function, further adding a sweetener, a flavoring agent, an antimicrobial preservative and a coloring agent, and determining their optimum concentration(s) in view of the known workable range(s) would have been well-known, routine and conventional to those skilled in the art. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, including the claimed ingredients and claimed concentration, because Harris et al. teaches the workable range of each pharmaceutically acceptable excipient, including citric acid, sorbitol, sweetener, preservative, and stabilizer; interchanging one art recognized pharmaceutically acceptable excipient with another of the same function, including interchanging disodium EDTA with disodium dihydrate EDTA (edetate disodium dihydrate) as stabilizer, saccharin with sodium saccharin as sweetener, bubble gum flavor with cherry flavor as flavoring agent; and further adding another preservative (sodium benzoate) and flavoring agent (FD&C Red No. 40) are routinely employed during the preparation of liquid formulation.
According to MPEP 2144.05, I, “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”; and further according to MPEP 2144.05, II, A, “[g]enerally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”. In the absence of any evidence demonstrating a patentable difference between the compositions and the criticality of the claimed concentration range, the determination of the optimum or workable concentration based the guidance of the prior art would have been generally prima facie obvious to the skilled artisan.
Regarding the limitation of “having a pH of 4.0 – 4.5” as claimed in claim 17, the claimed limitation is drawn to physical or chemical property of the oral solution. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by adjusting the pH of the oral syrup set forth above by optimizing the concentration of citric acid through routine optimization. One would have been motivated to do so, because Marchetti et al. teaches the solubility of trazodone hydrochloride is known to increase with increase in acidity of the aqueous medium. Accordingly, one would have reasonably expected that the pH of the oral syrup is a recognized known result-effective variable to improve physical property of the active ingredient, such as solubility. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, including the claimed pH, because Calisti et al. demonstrates the preparation of trazodone HCl oral syrups with a pH value of 4.5, and would reasonably expect that by adjusting the concentration of citric acid as the buffering system to arrive at an oral syrup with a lower pH, including 4.5, would have successfully improve the solubility of the trazodone hydrochloride.
Regarding the limitation of “free from visible particulate matters” as claimed in claim 16, the limitation of “having a specific gravity of 1.055 g/mL” as claimed in claim 18, and the limitation of “having a viscosity of less than 10 cP” as claimed in claim 19, each of these limitations are drawn to physical or chemical property of the oral solution. Even though the prior art does not explicitly teach the disclosed oral syrup is free from visible particular matters, has a specific gravity of 1.055 g/mL, and has a viscosity less than 10 cP, the above physical and chemical parameters depend, among other things, from the specific components, relative amounts, type of formulation, and pH of the formulation etc., all of which seem to be the same or very similar to the oral solution made obvious by the prior arts set forth above.
The office does not have the facilities and resources to provide the factual evidence needed in order to establish that the formulations will result from the teachings of the prior art does not possess the same material, structural and functional characteristics of the formulation claimed in the instant application. In the absence of evidence to the contrary, the burden is on the applicant to prove that the formulation used in the instantly claimed method is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Claims 1, 3, 5, 7, 9, 11, 13 and 15-20 are rejected under 35 U.S.C. 103 as being unpatentable over Calisti et al. (WO 2021/058810 A1), in view of Marchetti et al. (US 10,292,931 B2), Harris et al. (US 2012/0022094 A1), Chen et al. (WO 2007/067331 A1) and Levenson et al. (US 2007/0178123 A1) as applied to claims 1, 3, 5, 7, 9, 11, 13 and 15-19 above, and further in view of Fagiolini et al. (CNS Drugs, 2012. Vol. 26(12): 1033-1049) (newly applied as necessitated by amendment).
The teachings of Calisti et al., Harris et al., Chen et al., Levenson et al., and Marchetti et al. are set forth above and applied as before.
Although Calisti et al. teaches trazodone is an antidepressant with combined serotoninergic receptor antagonism and serotonin reputable inhibition that give rise to its potential use in a broad range of co-morbidities of major depressive disorder (see e.g., p. 1, line10-17), and it is indicated primarily for the treatment of depression in patients who do not respond to antidepressants, such as selective serotonin reuptake inhibitors (see e.g., p. 1, line 10-13), Calisti et al., Harris et al., Chen et al., Levenson et al., and Marchetti et al. does not expressly teach administering an effective amount of the oral solution to a human subject with major depressive disorder.
Fagiolini et al. teaches several randomized, controlled clinical trials of trazodone in adults with major depressive disorder were published since 1981 (see e.g., Table 1); and further teaches short-term therapy (4–6 weeks) with trazodone (100–400 mg) appeared to be comparable in efficacy to TCAs such as amitriptyline and imipramine (see e.g., p. 1035, left column, “Efficacy and Tolerability of Trazodone in MDD”). Fagiolini et al. further teaches trazodone is approved and marked in several countries worldwide for the treatment of major depressive disorder in adult patients; and it is an effective and well tolerated antidepressant with an important role in the current treatment of major depressive disorder both as monotherapy and as part of a combination strategy (see e.g., abstract). Fagiolini et al. further teaches trazodone is available in many countries worldwide in different formulations including immediate-release (IR) tablets, prolonged-release tablets and, in some countries, even as oral drops and solution for injection (see e.g., p. 1034, left column, 2nd last paragraph). Fagiolini et al. further teaches according to the appropriate trazodone summary of product characteristics, including trazodone hydrochloride (see title of citation number 31-33), therapy should begin with an evening administration (starting dose 75–150 mg before bedtime) (see e.g., 1035, left column, last paragraph). Please note adult patients of Fagiolini et al. are human subjects.
It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by administering the oral syrup of Calisti et al., Harris et al., Chen et al., Levenson et al. and Marchetti et al. set forth above at an effective amount to a human subject with major depressive disorder, because Fagiolini et al. teaches trazodone is approved and marked in several countries worldwide for the treatment of major depressive disorder, and it is an effective and well tolerated antidepressant with an important role in the current treatment of major depressive disorder both as monotherapy and as part of a combination strategy. One of ordinary skill in the art would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably understood that the hydrochloride salt of trazodone is useful for treating major depressive disorder; and therefore, by administering the oral syrup containing the same active pharmaceutical ingredient (trazodone hydrochloride) at an effective amount to a human subject with major depressive disorder, one would have expected to treat major depressive disorder.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Calisti et al. (WO 2021/058810 A1), in view of Marchetti et al. (US 10,292,931 B2), Harris et al. (US 2012/0022094 A1), Chen et al. (WO 2007/067331 A1) and Levenson et al. (US 2007/0178123 A1)(newly applied as necessitated by amendment).
Calisti et al. teaches sweeter formulations of trazodone are needed due to trazodone’s bitter taste (see e.g., p. 6, line 18-19). Calisti et al. further teaches multiple pharmaceutical suitable for oral administration (see e.g., p. 1, line 5-8; p. 15, line 5-7), including exemplary oral drop solutions containing 15 mg/mL (1.5% w/v) or 30 mg/mL (1.5 w/v) of trazodone HCl (see e.g., p. 16, line 3-7), and syrup compositions with pH value of about 4.5, such as syrup “Trial C” shown below (see e.g., Table 8; p. 22, line 1):
PNG
media_image1.png
484
312
media_image1.png
Greyscale
.
Calisti et al. further teaches “EDTA” is an abbreviation for disodium edetate (see e.g., Table 7).
Please note the weight-by-volume percentage, wherein 1% (w/v) means 1 gram of solute per 100 mL of solution, can be convert to mg/mL using the equation of:
m
g
m
L
=
%
(
w
/
v
)
×
10
; and by employing the unit conversion, the Trial C syrup of Calisti et al. comprising 2.6 mg/mL of trazodone hydrochloride, 0.56 mg/mL of citric acid, 100 mg/mL of sorbitol, 1.3 mg/mL of methylparaben, and 0.5 mg/mL of disodium edetate (EDTA). Calisti et al. further teaches the syrup compositions do preferably comprise a preserving agent which is preferably selected in the group comprising methyl and propyl parahydroxybenzoate, potassium sorbate and mixture thereof; and the preferred is potassium sorbate or, alternatively, sodium benzoate (see e.g., p. 12, line 17-23). Calisti et al. further teaches alternatively, syrup composition have a trazodone concentration of 0.1 to 0.9 mg% (w/v) (see e.g., p. 11, line 16-21). Calisti et al. further teaches the dosage forms can also contain other traditional ingredients such as: preservatives, stabilizers, surfactants, buffers, salts for regulating osmotic pressure, emulsifiers, sweeteners, colorants, flavourings and the like, suitable for pediatric use (see e.g., p. 15, line 15-18). Calisti et al. further teaches the invention is suitable for use in the treatment of insomnia in the pediatric population (see e.g., abstract).
Although Calisti et al. teaches an exemplary oral drop solutions containing 15 mg/mL (1.5% w/v) or 30 mg/mL (1.5 w/v) of trazodone HCl, and syrup composition Trial C comprising: 2.6 mg/mL of trazodone hydrochloride (see calculation above), citric acid, sorbitol, methylparaben, and disodium edetate, the prior art also does not expressly teach the motivation to incorporate 16.44 ± 3 mg/mL of trazodone hydrochloride; and does not does not expressly teach disodium edetate dihydrate, sodium saccharin.
Marchetti et al. teaches various liquid formulations, for oral use (drops, syrup) or parenteral use (vials for injection), with concentrations of trazodone hydrochloride equal to approx. 1 % (w/v), are being marketed; However, low concentration of trazodone involve counting a large number of drops to give the therapeutic dosage (see e.g., Col. 2, line 14-21 and 24-26). Marchetti et al. further teaches there is still a great need for a liquid pharmaceutical composition of trazodone hydrochloride for oral administration in which an amount of trazodone hydrochloride greater than or equal to 1 % (w/v) can be dissolved stably, does not contain ethanol as solvent or cosolvent, and does not turn yellow over time (see e.g., Col. 2, line 37-42). Marchetti et al. further teaches the solubility of trazodone hydrochloride in the presence of mixtures of cosolvents can reach concentration levels of the order of 10-15% (see e.g., Col.3, line 9-11); preferably, the liquid pharmaceutical composition comprises two cosolvents, each independently in an amount in the range from 5% to 50% (w/v) (see e.g., Col. 3, line 16-20); and at leave two solvent selected from the group glycols and polyglycols makes it possible to obtain a stable liquid composition (see e.g., Col. 7, line 4-8). Marchetti et al. further teaches the concentration of trazodone hydrochloride in the liquid pharmaceutical composition is preferably between 1 % and 15% (w/v) (see e.g., Col. 2, line 64-67).
Harris et al. teaches storage-stable syrup formulations, which contains only components recognized as being safe for human ingestion (see e.g., [0006]), including exemplary syrup formulation in Example 1 suitable for pediatric use shown below (see e.g., Example 1; [0024]; [0015]):
PNG
media_image2.png
513
370
media_image2.png
Greyscale
.
Harris et al. further teaches preferred buffering system includes citric acid buffer system, including citric acid, and those capable of maintaining a pH in the range of greater than about 4.5 (see e.g., [0016]). Harris et al. further teaches suitable pharmaceutically acceptable solvents and/or carrier system include water, alcohols and glycols, especially, inter alia, propylene glycol, sorbitol and/or polyethylene glycol; use of a combination of at least one of water, propylene glycol, sorbitol and glycerin is preferred (see e.g., [0015]). Harris et al. further teaches suitable non-sugar based artificial sweetening agents for use in the present invention include saccharin (see e.g., [0014]). Harris et al. further teaches sugar based syrup formulations it is often desirable to employ antimicrobial preservatives in order to protect a syrup against microbial growth; among the preservatives commonly used in the preservation of syrups with the usually effective concentrations are benzoic acid (0.1 to 0.2%), sodium benzoate (0.1 to 0.2%), and various combinations of methyl-, propyl-, and butylparabens (totaling about 0.1 %)(see e.g., [0018]). Harris et al. further teaches stabilizers may also be incorporated into the syrup formulation in order to make a stable single phase composition; and the alkali metal salts of ethylenediaminetetraacetic acid (“EDTA”) are preferred (see e.g., [0019]). Harris et al. further teaches most syrups are flavored with synthetic flavorants or with naturally occurring materials; and typical flavoring agents which are commonly used in sweetened pharmaceuticals, foods, candies, beverages are also useful in the present invention, including bubble gum (see e.g., [0021]). Harris et al. further teaches the antihistaminic syrup formulations of the present invention may also contain one or more other drugs for obtaining more than one therapeutic result from a single dose (see e.g., [0011]).
Chen et al. teaches the pharmaceutical formulations, including liquid dosage form such as oral syrup (see e.g., [0001]), containing at least one stabilizer to help improve the stability of d-penicillamine when in a liquid dosage form; and the preferred stabilizer is disodium EDTA or disodium dihydrate EDTA (see e.g., [0061]). Chen et al. further teaches artificial sweeteners may be include, but are not limited to saccharin, and the preferred artificial sweeteners are, inter alia, sodium saccharin (see e.g., [0057]), and sodium saccharin is a soluble saccharin salt from and water-soluble (see e.g., Table I, “Water-soluble Artificial Sweeteners”).
Although the prior arts do not expressly disclose each and every ingredient in the claimed mg/mL, converting between concentration format (e.g., from w/v to mg/mL; or from w/w to mg/mL) or determine the corresponding mg/mL concentration based on the density of the formulation would have been routine mathematical conversion within the ordinary skill of a pharmaceutical formulator. The prior art discloses the identity and relative amounts of the formulation components, and a person of ordinary skill in the art would have routinely determined the corresponding mg/mL concentration when preparing or optimizing the formulation. Therefore, expressing the composition in terms of mg/mL would have been an obvious matter or routine optimization and does not patentably distinguish the
claimed composition. The weight-by-volume percentage(s), wherein 1% (w/v) means 1 gram of solute per 100 mL of solution, can be convert to mg/mL using the equation of
m
g
m
L
=
%
(
w
/
v
)
×
10
, for example, 0.26 w/v % of trazodone hydrochloride, which when calculated by
0.26
g
100
m
L
×
1000
m
g
1
g
=
2.6
m
g
/
m
L
, gives 2.6 mg/mL of trazodone hydrochloride.
Regarding the recitation of “solvent consisting of water” followed by the phrase of “[a]n oral solution comprising” in claim 21, the transitional term “comprising” recites in the preamble of the claim is inclusive or open-ended and does not exclude additional, unrecited elements; and therefore, given its broadest reasonable interpretation, while the claim recites “solvent consisting of water”, the transitional “consisting” followed after “solvent” only limits one solvent to be water, and does not further limit the oral solution as a whole to exclude additional, unrecited solvent.
Regarding claim 21, the difference between the syrup composition Trial C of Calisti et al. (2.6 mg/mL of trazodone hydrochloride, citric acid, sorbitol, methylparaben, and disodium edetate) and the claimed invention is that prior art does not expressly teach 16.44 ± 3 mg/mL of trazodone hydrochloride, and does not expressly teach the incorporation of sodium benzoate, edetate disodium dihydrate, sodium saccharin. However, Marchetti et al. teaches there is a need for liquid formulations with an amount of trazodone hydrochloride greater than or equal to 1 % w/v, which is greater or equal to 10 mg/mL, that can achieve therapeutic dosage with fewer drops/smaller volume, and teaches the use of at least two cosolvents comprising glycols and polyglycols can obtained a stable liquid composition of trazodone hydrochloride at concentration between 1% and 15% (w/v), which gives 10 mg/mL to 150 mg/mL of trazodone hydrochloride. Harris et al. teaches storage-stable oral syrup formulations comprising a combination of pharmaceutically acceptable solvents, including formulations comprising citric acid, sorbitol, saccharin, edetate disodium, saccharin, flavoring agents and water; and further teaches sodium benzoate and various combinations of methyl-, propyl-, and butylparabens are antimicrobial preservatives that can be added to protect syrup from microbial growth. Chen et al. teaches disodium dihydrate EDTA is a preferred alternated stabilizer on a par with disodium EDTA, and sodium saccharin is a preferred artificial sweeteners and a water-soluble salt form of saccharin. In view of the foregoing, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by 1) modifying the oral syrup composition Trial C of Calisti et al. in view of the oral syrup formulation taught by Harris et al. by adding a sweetener (saccharin) and another antimicrobial preservative (sodium benzoate), 2) substituting one art recognized pharmaceutically acceptable excipient with another of the same function as taught by Chen et al., i.e., substituting edetate disodium (EDTA) with disodium dihydrate EDTA (edetate disodium dihydrate) in order to arrive at an oral syrup composition comprising trazodone hydrochloride at a concentration of 10 mg/mL to 150 mg/mL that can achieve therapeutic dosage with fewer drops/smaller volume as taught by Marchetti et al. One would have been motivated to do so, because Marchetti et al. teaches the solubility of trazodone hydrochloride in the presence of mixtures of cosolvent can reach a concentration between 1% and 15% (w/v), which is 10 to 150 mg/mL of trazodone hydrochloride; and Harris et al. teaches an oral syrup that can contain one or more other drugs in addition to the desloratadine disclosed therein, comprising more than one pharmaceutically acceptable solvents (including sorbitol and water), citric acid, sweetening agent (saccharin), antimicrobial preservatives (including sodium benzoate, and methylparaben), stabilizer (edetate sodium); and Chen et al. teaches interchanging disodium EDTA with disodium dihydrate EDTA as stabilizer, and sodium saccharin with saccharin as artificial sweetener is well-known and routine in the art. Accordingly, one would have reasonably recognized the concentration of trazodone hydrochloride are result-effective-variable during the preparation of oral syrup to achieve the therapeutic dosage; and adding additional sweetener, additional antimicrobial preservatives and interchanging one art recognized pharmaceutically acceptable excipient with another of the same function would have been well-known, routine and conventional to those skilled in the art. One would have a reasonable expectation of success to arrive at the claimed invention, including the claimed concentration, through routine experimentation, because Harris et al. demonstrates a successful preparation of an stable oral syrup that incorporates citric acid, sorbitol, saccharin, edetate disodium, water; and Calisti et al. and Harris et al. both teaches the oral syrup can add antimicrobial preservatives, including sodium benzoate and methylparaben. One would have reasonably recognized adding sodium benzoate and methylparaben as preservatives, and interchanging one art recognized pharmaceutically acceptable excipient with another of the same function, including interchanging disodium EDTA with disodium dihydrate EDTA (edetate disodium dihydrate) as stabilizer, saccharin with sodium saccharin as sweetener can successfully be employed during the preparation of liquid formulation. In the absence of any evidence demonstrating a patentable difference between the compositions and the criticality of the claimed dosage range, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan.
According to MPEP 2144.05, I, “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”; and further according to MPEP 2144.05, II, A, “[g]enerally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”.
Regarding the limitation of “further comprising colorant” in claim 22 and the limitation of “further comprising flavor” in claim 23, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the oral syrup set forth above by adding colorant or flavor, because Calisti et al. teaches the dosage forms can also contain other traditional ingredients such as colorants and flavourings. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the oral syrup can further contain colorant and flavor without any appreciable loss of activity.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Response to Arguments
Applicant's arguments filed on June 15, 2025 with respect to the rejection of claims 1-19 under 35 U.S.C. 103 as being unpatentable over Calisti et al. (WO 2021058810 A1), in view of Rowe et al. (Pharmaceutical Press, 6th Edition: pp. 61-63, 242-244, 441-445, 627-629, 679-682), Marchetti et al. (WO 2009016069 A2), Meeks (Medical News Today, 2021: 1-3), FDA Staff (FDA.gov, 2010: 2-4), and Sharma et al (Ancient Science of Life, 1998. Vol. VIII(1): 39) have been fully considered.
Applicant's arguments filed on June 15, 2025 with respect to the rejection of claims 1-5, 8-9, and 14-20 under 35 U.S.C. 103 as being unpatentable over Marchetti et al. (WO 2009016069 A2), in view of Promises Behavioral Health Editorial Team (Promises Behavioral Health, 2012: 2), Rowe et al. (Pharmaceutical Press, 6th Edition, pp. 242-244), FDA Staff (FDA.gov, 2010: 2-4), and Sharma et al (Ancient Science of Life, 1988. Vol. VIII(1): 39) have been fully considered.
Applicant amends independent claim 1, drawn to an oral solution, by incorporating the specific concentration range to trazodone hydrochloride, citric acid, sorbitol, sodium saccharin, sodium benzoate, methylparaben and edetate disodium dehydrate; However, it is respectfully noted that the instant concentration range for sorbitol, i.e., “175 ± 17.5 mg/ml sorbitol” is not recited in the prior-filed claims dated November 14, 2023, and said concentration range is a narrower than the limitation of “sorbitol is present in 357 ± 35.7 mg/mL” recited in previous claim 6, which is now canceled. Therefore, the claim amendment changes the scope of the claims, and necessitates a modification of the rejection(s) of record, including prior arts. Applicant also newly added claims 21-23, in which claim 21 is an independent claim that is not previously introduced; therefore, the rejection of record has also been revisited, and modified in view of the newly added claims.
In Summary, Applicant argues the claimed compositions with pH range of 4.0 to 4.5 are physically, chemically, and microbiologically stable over a shelf like of at last 6 months by directing attention to Examples 5 and 6 of instant specification (see e.g., p. 6, last paragraph in the reply). Applicant argues Calisti et al. discloses that selecting the right co-solvents is important for overcoming solubility issues, and identifies polyethylene glycol (PEG) 400 and propylene glycol as the preferred co-solvent; and further argues that compositions of Calisti et al. (e.g., Syrup #6 and syrup C), including sorbitol and methylparaben as additional ingredients, have much lower trazodone concentration (2.6 mg/ml of trazodone) and are unstable; and that teaches away from the claimed invention, because Calisti et al. teaches trazodone is only reasonably soluble when at least 2 other cosolvents are present. Applicant further argues Marchetti et al. fails to disclose the use of sorbitol or methylparaben at all and reinforces the use of cosolvents, including one or both of a glycol and a polyglycol; therefore, modifying Calistil et al. with Marchetti et al. still arrives at a trazodone composition that lacks sorbitol and methylparaben, which are required features of the claims; and teaches away from the composition as claimed in newly added claim 21. Applicant further argues No combination of Rowe, Meeks, FDA Staff, Sharma, and Promises Behavioral Health Editorial Team remedies the defects of the combination of Calisti et al. and Marchetti et al.; even though if a person having ordinary skill in the art would have look into the remaining cited reference for additional ingredients, none of them alone or in combination provide a reasonable expectation of success to arrive the claimed invention that contains both sorbitol and methylparaben.
In response, applicant’s arguments are not found persuasive for the reasons set forth below:
First, applicant’s assertion of unexpected results is not commensurate in scope with the claimed invention. According to MPEP 716.02(d), “whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the ‘objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.’ In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)”.
In the present case, applicant argues unexpected results (“[t]he claimed compositions have a pH of 4.0 to 4.5. As shown in Examples 5 and 6, such compositions are physically, chemically, and microbiologically stable over a shelf life of at least 6 months”; see page 6, last paragraph of the reply) are demonstrated in Examples 5 and 6 of instant specification. Specifically, Example 5 discloses a stability testing report of 25 mg/mL trazodone hydrochloride oral solution at room temperature for 180 days (see e.g., p. 23 of instant specification); and said oral solution has an initial pH value of 3.2, an initial viscosity of 1.0450, an initial gravity of 3.9 cP (see e.g., p. 24 of the instant specification). Example 6 discloses another stability testing report of 25 mg/mL trazodone hydrochloride oral composition for 180 days (see e.g., p. 28 of instant specification); and said oral solution has an initial pH value of 3.2, an initial viscosity of 1.0450, an initial gravity of 3.9 cP (see e.g., p. 30 of the instant specification). The specification does not expressly disclose the ingredients contain therein nor disclosed the concentration of each and every ingredient in the unit of mg/mL.
In contrast, claim 1 broadly recites an oral solution that does not contain trazodone hydrochloride at the same concentration. Specifically, instant claim 1 broadly recites an oral solution comprising: (i) 16.44 ± 1.6 mg/ml trazodone hydrochloride; (ii) 2.4 ± 0.24 mg/ml citric acid; (iii) 175 ± 17 .5 mg/ml sorbitol; (iv) 1.5 ± 0.15 mg/ml sodium saccharin; (v) 1.0 ± 0.1 mg/ml sodium benzoate; (vi) 1.0 ± 0.1 mg/ml methylparaben; (vii) 3.0 ± 0.3 mg/ml edetate disodium dihydrate; (viii) FD & C Red No. 40; (ix) cherry flavor; and (x) water. In other words, instant claim 1 encompassing a wide variety of oral solutions comprising any amount of FD &C Red No. 40, cherry flavor and water; and having any pH, specific gravity and viscosity. It is noted that the unexpected result applicant relies upon are exemplified using a specific concentration of trazodone hydrochloride, i.e., 25 mg/mL of trazodone hydrochloride rather than 16.44 ± 1.6 mg/mL of trazodone hydrochloride, and that does not provide adequate basis for concluding that similar results would be obtained for other concentration of trazodone hydrochloride. In addition, applicant only exemplify said stability result using two trazodone HCl oral compositions that has the same pH value of 3.2, the same viscosity of 1.0450, and the same gravity of 3.9 cP, and that also does not provide adequate basis for concluding that similar results would be obtained for oral solution having other pH value, other viscosity and/or other gravity. The specification also does not expressly disclose the ingredients contain therein other than 25 mg/mL of trazodone hydrochloride; and the concentration of each and every ingredient remain unclear.
Applicant cannot simultaneously rely on oral solutions comprising different concentration of trazodone hydrochloride, i.e., 25 mg/mL to establish relevance of the data while asserting that the claimed oral solution comprising 16.44 ± 1.6 mg/mL of trazodone hydrochloride exhibits unexpected properties. These finding demonstrates that applicant’s assertion of unexpected results is not commensurate in scope with the claimed invention; and therefore, the arguments are not found persuasive.
Second, it may well be true that Calisti et al. discloses that selecting the right co-solvents is important for overcoming solubility issues, and identifies polyethylene glycol (PEG) 400 and propylene glycol as the preferred co-solvent; However, according to MPEP 2141.02, V, “[a] prior art reference must be considered in its entirety, i.e., as a whole, including portions that would lead away from the claimed invention. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983), cert. denied, 469 U.S. 851 (1984)”. In other words, the mere fact that Calisti et al. teaches polyethylene glycol (PEG) 400 and propylene glycol are preferred co-solvents that can be employed to formulate oral compositions, it does not constitute a teachings away from a broader disclosure or nonpreferred embodiments to utilize other co-solvents to dissolve the active pharmaceutical ingredient, i.e., trazodone hydrochloride. Instead, Calisti et al. clearly disclosed syrup composition “Trial C” (comprising: 2.6 mg/mL of trazodone hydrochloride, 0.56 mg/mL of citric acid, 100 mg/mL of sorbitol, 1.3 mg/mL of methylparaben, and 0.5 mg/mL of disodium edetate) complies with the solubility testing of active pharmaceutical ingredient (see e.g., Table 8, Trial C, “solubility of API”); In other words, applicant’s assertion that compositions comprising sorbitol and methylparaben cannot dissolve trazodone hydrochloride at a concentration great then 2 mg/mL appears to be mere argument without supporting evidence. While Calisti et al. discloses syrup composition “Trial C” does not comply with physical stability testing at 4 °C, it is respectfully noted that the stability testing disclosed in Example 5 and 6 of instant specification as directed by applicant does not perform said testing under the same condition, i.e., 4 °C.; rather, the stability testing performed by applicant is conducted under room temperature. In other words, the evidence of unexpected properties, i.e., stability testing, presented by the applicant are not in the form of direct or indirect comparison of the claimed invention with the closest prior art under the same condition; in fact, the unexpected properties applicant relies upon contains a different concentration of trazodone hydrochloride (25 mg/ml) that does not lie within the claimed concentration range; therefore, these arguments are not found persuasive.
Third, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, applicant improperly evaluate each reference individually rather than considering the combined teachings of the reference as a whole. It is respectfully noted that applicant presents arguments specifically against Calistil et al. and Marchetti et al. alone and in combination rather than all the cited prior arts together. For instance, applicant argues Marchetti et al. fails to teach sorbitol and methylparaben when the rejection already established these ingredients using the oral composition taught by Calisti et al. It is respectfully noted that the obviousness-type rejection under 35 U.S.C. 103 does not require that each and every claimed limitation be disclosed within a single reference nor require that each and every claimed limitation be disclosed within two references together. Rather, the issue is whether the collective teachings of the prior art(s) would have suggested the claimed invention to one of ordinary skill in the art with a reasonable expectation of success.
Lastly, in response to applicant’s argument that the recitation of “(vi) solvent consisting of water” followed by “[a]n oral solution comprising” in claim 21 excludes additional, unrecited solvent(s) are not found persuasive, it is respectfully noted that the transitional term “comprising” recites in the preamble of the claim is inclusive or open-ended and does not exclude additional, unrecited elements; and therefore, given its broadest reasonable interpretation, while the claim recites “solvent consisting of water”, the transitional “consisting” followed after “solvent” only limits one solvent to be water, and does not further limit the oral solution as a whole to exclude additional, unrecited solvent.
In view of the foregoing, applicant’s arguments have been fully considered but they are not found persuasive. Since the amendment changes the scope of the claims, the previous rejection of record has been withdrawn; However, upon further consideration, a new ground(s) of rejection is made in view of the prior arts cited herein and for the reasons set forth herein.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Chihyi Lee whose telephone number is (571)270-0663. The examiner can normally be reached Monday - Friday 8:30 am - 5:00 pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L. Clark can be reached at (571) 272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628
Prosecution Insights