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 .
Election/Restrictions
Applicant's election with traverse of Group I, said to now correspond to new claims 14-18 & 20-24, in the reply filed on 8/21/2024 is acknowledged. The traversal is on the ground(s) that Group II depends from the elected claims. This is not found persuasive because: The Restriction Requirement established that the inventions (set forth in the claims the Requirement was based on) failed to share a single general inventive concept, as set forth at Item 5 of the Restriction Requirement. Thus, restriction between the invention groups was set forth properly. Additionally, the elected claims are not currently allowable, and do not satisfy the conditions for rejoinder, stated at Item 7 of the Restriction Requirement, mailed 4/2/2024.
The requirement is still deemed proper and is therefore made FINAL.
Applicant's election with traverse of the composition of Example 1:
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806
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in the reply filed on 8/21/2024 is acknowledged. The traversal is on the ground(s) that see above. This is not found persuasive because see above.
The requirement is still deemed proper and is therefore made FINAL.
Claims 19 & 25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 8/21/2024.
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.
Claim(s) 14-18, 20-24, 26-33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Public Drug Database of France (LAROXYL 40 mg/ml, oral solution – Patient information leaflet; Patient Information Leaflet - LAROXYL 40 mg/ml oral solution - Public Medicines Database (medicaments.gouv.fr); accessed 10/7/2023; cited in a prior Office action); in view of Garwood (“Osmotic Diuretics”; Chapter 104; in Critical Care Nephrology (Second Edition), 2009); IDS 4/11/2024 reference in child Application No. 18/310,575; cited in a prior Office action), Ford (US 2002/0028789 A1; 2002; cited in a prior Office action); and Wockhardt (“Package leaflet: Amitriptyline Hydrochloride 25 mg/5ml and 50 mg/5 ml oral solution”; revised in 2018, according to the wayback machine capture on 20 Oct 2021; https://web.archive.org/web/20211020105814/https://www.medicines.org.uk/emc/files/pil.2350.pdf, evidencing this reference was published in 2018; cited in a prior Office action); European Medicines Agency (“Questions and Answers on Ethanol in the context of the revision of the guideline of ‘Excipients in the label and package leaflet of medicinal products for human use’ (CMP/463/00)”; 2014, pp. 1-14; https://static.poder360.com.br/2024/07/Agencia-Europeia-de-Medicina-.pdf; accessed 11/16/2024; cited in a prior Office action); and Ezealisiji et al. (“Aqueous Solubility Enhancement of Mirtazapine: Effect of Cosolvent and Surfactant”; 2015; Pharmacology & Pharmacy; 6: 471-476).
Examiner notes the LAROXYL 40 mg/mL page was published prior to the October 1, 2017 snapshot of the Wayback Machine; web.archive.org/web/20171001122852/https://base-donnees-publique.medicaments.gouv.fr/affichageDoc.php?specid=68969066&typedoc=N; accessed 10/7/2023; the 2017 webpage gives a date of last update 10/30/2012, construed that this document was published on or prior to this 2012 date. Both documents were translated into English by the translate option in the Microsoft Edge browser.
LAROXYL 40 mg/ml, oral solution teaches this 40 mg/ml concentration of amitriptyline was available as a drug to patients in 2012. The active substance is amitriptyline hydrochloride, corresponding to amitriptyline for 1 ml of oral solution (section 6); other components are ethyl alcohol at 95%, glycerol and purified water (section 6). Examiner notes that the box in section 2.0 indicates ethanol concentration was 11.99% (v/v).
Thus, this prior art product contains the recited concentration of amitriptyline HCl required by claims 14 & 20, and contains claimed/elected components glycerol and water. The oral solution satisfies the form of a liquid oral solution, required by claims 14 & 20. The ethyl alcohol component is excluded by the negative recitation of claim 14; ethanol as an antioxidant or preservative does not fall within the alternatives recited in claim 20; because of the closed construction of claim 20, the ethanol containing embodiment of LAROXYL 40 mg/mL forms a construct outside of this claim. This publication does not teach a concentration or concentration range of glycerol, and there is no mention of a surfactant, nor Applicant elected polysorbate 80 (aka, Tween 80). The listing of claim 14, lines 5-6 is not satisfied by the components taught, and the listing of claim 20 lines 5-7, within the wherein clause limitations of this claim are not satisfied by components taught. This reference does not teach Applicant elected sucralose nor a generic flavoring agent nor a specie within Applicant elected genus of flavoring agent.
Garwood teaches glycerin [aka, glycerol] may be given orally as a 10% solution. While administration of intravenous solutions with higher concentrations can lead to hemolysis, oral administration of glycerin at concentrations of 50% of greater does not appear to be associated with this adverse event. Garwood establishes that suitable concentration range of glycerol in liquid oral solutions ranges from 10-50% (about 100 mg/mL to about 500 mg/mL, which overlaps with the range of claims 14 & 20, and encompasses ranges of claims 15, 16, 21, 22, rendering the ranges of these claims prima facie obvious from the overlapping range, or from within the prior art range (MPEP 2144.05 (I)), and also, alternatively, as a result of routine optimization of prior art amounts (MPEP 2144.05 (II)(A)).
MPEP 2144.05(I): In 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) …
"[A] prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness." In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003).
MPEP2144.05 (II)(A): Generally, 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 re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Examiner notes there is no evidence on the record of criticality of any claimed range.
Regarding polysorbate 80 (aka Tween 80), Ford teaches cream-type carriers for topical delivery of medicaments, and includes amitriptyline hydrochloride, in combination with the carrier. Examiner notes that Tween 80 and glycerin are both taught as components of the cream carrier (abstract). Tween 80 is taught to function as an emulsifier [0008], and is combined with, inter alia, glycerin [0009] and water [0016]. The skilled artisan would have recognized the benefit of Tween 80, an emulsifier/surfactant, to modify LAROXYL oral solutions. Review of amounts in Example 1 of Ford, depict Tween 80 present in about 2.899% (2.899 mg/100mg or 0.3 mg/g; presuming liquid densities for liquid ingredients of about 1 g/mL); i.e., about 0.3 mg/mL, close to the range of claims 14 & 20, similar enough to be prima facie obvious over about 1 mg/mL (claimed 0.9-1.1 mg/mL range) as being close (MPEP 2144.05 (I), 2nd paragraph), and as a starting point for routine optimization of the surfactant/emulsifier component to optimize LAROXYL oral solutions with obvious added polysorbate 80, the claimed amount considered obvious, as a result of routine optimization (MPEP 2144.05 (II)(A)). Other cream components would not be considered as needed, based on the differences between solutions and cream formulations.
MPEP 2144.05(II)(A): Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). See also Warner-Jenkinson Co., Inc. v. Hilton Davis Chemical Co., 520 U.S. 17, 41 USPQ2d 1865 (1997) (under the doctrine of equivalents, a purification process using a pH of 5.0 could infringe a patented purification process requiring a pH of 6.0-9.0); In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%); In re Waite, 168 F.2d 104, 108, 77 USPQ 586, 590 (CCPA 1948); … In re Dreyfus, 73 F.2d 931, 934, 24 USPQ 52, 55 (CCPA 1934); In re Lilienfeld, 67 F.2d 920, 924, 20 USPQ 53, 57 (CCPA 1933)(the prior art teaching an alkali cellulose containing minimal amounts of water, found by the Examiner to be in the 5-8% range, the claims sought to be patented were to an alkali cellulose with varying higher ranges of water (e.g., "not substantially less than 13%," "not substantially below 17%," and "between about 13[%] and 20%"); K-Swiss Inc. v. Glide N Lock GmbH, 567 Fed. App'x 906 (Fed. Cir. 2014)(reversing the Board's decision, in an appeal of an inter partes reexamination proceeding, that certain claims were not prima facie obvious due to non-overlapping ranges);
Examiner notes that the difference between about 0.3 mg/mL and the claimed range of 0.9-1.1 mg/mL is a factor of 3 to 3.7. Similar factors are present among cases where prior art amounts were found to be close. For example, in the In re Aller case 10% acid concentration relative to 25-70%, the factor is 2.5-7. In the Lilienfeld case the 5-8% prior art range relative to the “not substantially below 17%” claim limitation is a factor of 2.1-3.4. Thus, the instant case is similar to these cases; the 0.3 mg/mL prior art amount of polysorbate 80 is close enough to the claimed range to be considered prima facie obvious.
However, the rejection alternatively establishes that routine optimization would have been found to render the claims prima facie obvious, to determine a workable polysorbate 80 concentration, as a result of routine optimization, when it is present as an emulsifier/surfactant. Examiner notes there is no established criticality of the claimed 0.9-1.1 mg/mL range of polysorbate 80 recited.
European Medicines Agency teaches guidelines on ethanol, when used as an excipient in medicinal products for human use (title). Ethanol is used as a solvent to improve drug solubility (33). Ethanol can be found as a solvent in numerous oral liquid formulations and OTC medicines such as cough and cold medicines (44-45). Safety concerns associated with ethanol are discussed in section 4. It is important to note that the effect of long term exposure to even low levels of ethanol in medicines on the health and development of children has not been evaluated, but there is direct evidence of grave deleterious effects of chronic ethanol exposure, for example, on neurological and cognitive developmental processes (72-76). Moreover, ethanol use in adult medicines is discouraged for a number of other reasons including interactions with other medicines, diseases, effect on driving performances, issues with addiction, pregnancy and breast feeding (77-79).
Ethanol should not be included in medicinal products intended for children unless necessary (86-87). The FDA also recommends not including ethanol in medicinal products intended for use in children (92).
Ethanol should not be included in medicinal products, unless justified; as part of the justification for the use of ethanol there should be a discussion of why other excipients cannot fulfil the functions of ethanol in the formulation (104, 108-109).
European Medicines Agency establishes a preference for removing ethanol from formulations, such as the ethyl alcohol in the LAROXYL 40 mg/ml oral formulation. Because ethanol is art recognized cosolvent, the skilled artisan would have been motivated to substitute a surfactant/emulsifier, in an effort to reformulate these oral formulations.
Because ethanol is often used as a cosolvent in solutions, the skilled artisan would have been motivated to explore reduction or removal of ethanol content with the introduction of the surfactant/emulsifier material polysorbate 80. The skilled artisan would have further consulted formulations of tablets of Amitriptyline HCl, which include Elavil; these tablets include Polysorbate 80 (see https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=84600bfc-bcbf-4b37-a575-a6a99e2434fd&type=display; 2015; accessed 10/7/2023). The skilled artisan would have surmised that polysorbate 80 provides a benefit for dissolution of Amitriptyline HCl tablets, likely based on surfactant properties solubilizing this active agent. In addition to the Elavil formulation considerations, teachings of Ford provide additional motivation to add polysorbate 80, in amounts within and similar to those claimed, rendering this component obvious, rendering obvious the required combination of amitriptyline HCl in the concentration of 40 mg/mL, glycerol in overlapping amounts, and amounts encompassing claimed ranges, rendering claimed ranges obvious, and polysorbate 80 amounts close to and rendering obvous the amounts of the instant claims.
Regarding the elected sweetener, a skilled artisan would have reviewed other Amitriptyline oral solutions for consideration of ingredients taught in other amitriptyline oral solutions; Wockhardt teaches oral solutions of Amitriptyline. Section 6 lists that other ingredients include sucralose powder. Accordingly, it would have been obvious to one or ordinary skill in the art at the time of the instant application effective filing date, to include sucralose as a sweetener to the LAROXYL oral solutions, giving the elected embodiment of the instant claims. The motivation would have been to incorporate a sweetening agent known in the art to sweeten amitriptyline oral solutions.
Regarding Applicant elected flavoring agent, the Wockhardt formulations include orange flavor, orange/tangerine flavors (section 6), rendering obvious flavors (but without the ethanol, motivated by the European Medicines Agency), giving embodiments containing both a flavoring agent and a sweetener, in addition to the amitriptyline HCl, glycerol, and polysorbate 80, in amounts obvious over the instant claims 14-16 & 20-22.
Regarding pH, the rejection establishes that each of the elected components (corresponding to disclosed Example 1) are prima facie obvious. The instant disclosure indicates that the pH of this formulation is about 4.5. Accordingly, for the instant obvious formulation, absent evidence to the contrary, the pH would characteristically have the same (or close to, obvious over) the claimed pH ranges of claims 17-18, 23-24.
Ezealisiji teaches a study about aqueous solubility enhancement of Mirtazapine, studying the effect of cosolvent and surfactant (title). Mirtazapine, a tetracyclic antidepressant used for treatment of moderate to severe depression and anxiety, has poor aqueous solubility. The objective of the study was to investigate the effect of solubilizing agents (cosolvents and surfactants) on the aqueous solubility of mirtazapine while envisaging that any significant improvement in its aqueous solubility could contribute towards alleviating the withdrawal symptoms often associated with the drug.
Cosolvency is discussed starting 472, 2nd paragraph: (mixing a permissible non-toxic organic solvent with water) is the most common and feasible technique to enhance the aqueous solubility of drugs. The most common cosolvents utilized are glycerin, ethanol, polyethylene glycols, et cetera. Surfactants (amphiphilic molecules composed of a hydrophilic moiety known as the head and a hydrophobic moiety known as the tail) have been reported to solubilize a number of poorly water soluble drugs. They do that by forming colloidal clusters in solutions called micelles. As association colloids, micelles can form spontaneously under certain conditions (self-assembling system) and are thermodynamically more stable towards both dissociation and aggregation. Literature review has revealed that mirtazapine is practically insoluble in water and that no study on the enhancement of the drug’s aqueous solubility by cosolvency and micellization has been reported. Therefore, we took to investigate the extent to which the aqueous solubility of mirtazapine could be enhanced by cosolvents (propylene glycol, polyethylene glycol 400) and surfactants (sodium lauryl sulfate, polysorbate 20, polysorbate 80) while envisaging that the aqueous solubility enhancement could potentially alleviate the drug problems that contribute to its withdrawal symptoms. (472, 2nd paragraph).
The chemical structure of mirtazapine is shown at bottom of 472. This tetra cyclic compound is similar to the instant compound, amitriptyline, a tricyclic compound, having antidepressant properties.
Table 1 depicts concentrations of cosolvents and comparable concentrations of surfactants, including polysorbate 80:
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The table depicts 10% of cosolvent (about the ethanol amount documented in the rejection) which lines across to 0.10 % w/v Polysorbate 80 achieves similar solubilities.
Ezealisiji notes that the minimum drug solubility is not sufficient to formulate oral liquid or parenteral dosage forms of mitazapine, but could be incorporated into solid dosage forms as excipients (475-476, bridging paragraph).
The skilled artisan would have taken note of the testing procedures and comparative cosolvent concentrations to the surfactant concentrations, providing a basis for selecting 0.10% w/v (a.k.a., 1 mg/mL; the concentration recited for polysorbate 80 in claim 1), and guidance for routine optimization of determining workable amounts of, inter alia, polysorbate 80, when substituted for ethanol in formulating a liquid oral solution of amitriptyline HCl.
Regarding new claims 26-33, consider claim 16, which is limited to about 380 mg/mL glycerol (38% w/v), 4% amitriptyline, and 0.1% polysorbate, attributing 0.5% to the added excipients, estimate of water (based on an assumption of additive volumes) would be 100-4-38-0.1-.5=57.4% water. The ratio of water to glycerol is 57.4:38 or 1.51, within each ratio of claims 26-29, 31-33. Regarding claim 29, use of a smaller amount of glycerol, say 30% (300 mg/ml), the amount of water would be 65.4, based on similar assumptions, giving a ratio of about 2.18, close to and rendering obvious the claim 29 ratio. Likely, the volume of water is a little higher because of solvent miscibility, giving a claimed ratio, say 70:30, or 75:30 within the range of claim 29. In any case, each of the recited ratios of water:glycerol is obvious, within recited amounts, and as a result of routine optimization based on amounts obvious from the prior art. In any case, the Examiner did not identify any criticality of any ratio of these claims.
Applicant argues that the EMA Notice does not suggest removing alcohol, but rather, at most suggests revisiting the Laroxyl 40 label content with respect to alcohol, and, even if motivated to exclude alcohol from Laroxyl 40 does not suggest replacing Laroxyl 40’s alcohol with a surfactant/emulsifier. Further, amitriptyline HCl is freely soluble in water; the amount of polysorbate 80 is alleged to be about 30 mg/mL, which exceeds the Office’s estimated about by about 100-fold.
Regarding removal of alcohol, EMA clearly teaches “Ethanol should not be included in medicinal products, unless justified…As part of the justification for the use of ethanol there should be a discussion of why other excipients cannot fulfil the functions of ethanol in the formulation” (104, 108-109). According to the French Medicines Agency, ethanol should not be included in medical products intended for children unless necessary (86-87); The FDA also recommends not including ethanol in medicinal products intended for use in children (92). While this article does discuss low levels of ethanol, the rejection relies on the preferred embodiment that ethanol should not be included in medicinal products. The “unless justified” embodiment is considered an alternate embodiment, less preferable. Thus, Applicant’s arguments are not correct, because the preferable non-inclusion of ethanol is clearly taught.
Examiner has reviewed the Laroxyl 40 labeled, but does not find any discussion of why (justification for) ethanol is used, and why other excipients cannot fulfill the functions of ethanol. Additionally, dosing to children is clearly contemplated by the Laroxyl 40 label; thus, the FDA recommendation of ethanol not being included is clearly pertinent, and considered preferred for the children embodiment.
Ethanol is clearly taught as a solvent, for solubilizing drugs (EMA, 33), and also functions as an antimicrobial preservative (EMA, 50). Replacement of ethanol by a surfactant/emulsifier, including explicitly polysorbate 80, is clearly suggested by the considerations of Ezealisiji. About 10% of cosolvent is comparable to about 0.10 % of polysorbate 80, based on similar solubilities with mirtazapine. However, the concentrations tested for polysorbate 80 include a range from 0.05% to 2.0, including testing the explicit concentration of 0.10 % w/v. i.e., 1 mg/mL. Thus, the claimed concentration is obvious from the prior art testing of this and the broader range that encompasses this concentration.
Regarding the argument that amitriptyline HCl is freely soluble in water, the Examiner notes that addition of other excipients can affect solubility. Because the Laroxyl 40 used ethanol, the skilled artisan would have found it obvious to review Ezealisiji experiments to inform testing of the substitute surfactant/emulsifier polysorbate 80, and to optimize the concentration of this component. Ezealisiji make clear that cosolvents and surfactant / emulsifier including polysorbate 80 are typical in the prior art consideration of an alternate compound, with similar structural characteristics, which is also an antidepressant.
Applicant argues extensively on reasons that the EMA notice would not have suggested removal ethanol. The Examiner does not dispute the citations from the EMA, but demonstrates above that EMA notice has preferred removal of ethanol, which is relied on. MPEP 2123 make clear that patents are relevant as prior art for all they contain.
Regarding the argument that amitriptyline HCl is freely soluble in water, and states a 100-1000 mg.mL solubility range, the Examine has also reviewed solubility in SciFinder, which is 100 g/L (100 mg/mL):
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While this level is higher than the claimed 40 mg/mL level recited in claim 14, the additional components of the claim, glycerol, and one or more of 6 classes of functionally defined excipients, may result in changing the solubility range of this drug. The naturally obvious substitution of polysorbate 80 for ethanol would have provided assurance of full solubilization in the presence of multiple excipients.
Regarding the argument that one (of ordinary skill in the art) would not replace the alcohol in Laroxyl 40 with polysorbate 80 based on a showing that a single tablet product includes polysorbate. The teachings of Ezealisiji provide motivation to test polysorbate 80 for sufficient enhancement of the active compound in a liquid oral solution, containing up to 6 additional, unspecified (except functionally) excipients. Ezealisiji clearly links testing in solution of polysorbate 80 to use in a tablet (when concentration is not high enough for solution of the active, the finding is made that polysorbate 80 would be suitable for oral dosage forms, including tablets).
Regarding the tablet information presented on p. 15, the rejection does not rely on any of these products, and cannot be used to establish teaching away.
Regarding the argument at g, there is no basis to utilize the same amount of polysorbate 80 as 11.9% ethanol. The concentration of cosolvent at 10% is matched to polysorbate 80 at 0.10% in the table of Ezealisiji.
Regarding the difference in amount of polysorbate 80 from the cream type formulation of Ford, the Examiner notes that following Ezealisiji gives a range of polysorbate 80, that renders obvious the claimed polysorbate 80 amount. The Examiner notes that the Ford formulation amount is probably better estimated by Applicant than previously stated by the Examiner. However, the amounts taught by Ezealisiji provide a better basis for use in an oral liquid form, which includes 0.10 % w/v (1 mg/mL) among tested polysorbate 80 amounts obvious to test.
Applicant argues about a glycerin to Tween 80 ratio of glycerol to polysorbate 80 according to Ford. While there is mention of scaling up or down using equivalent ratios (claim 2), there is no singling out of the glycerin/Tween 80 ratio. In fact, claim 14 does not recite this argued ratio. The amount 1 mg/mL for polysorbate 80 is taught by Ezealisiji, which also provides a basis for optimization to determine workable amounts. The amount of glycerol is informed: Garwood establishes that suitable concentration range of glycerol in liquid oral solutions ranges from 10-50% (about 100 mg/mL to about 500 mg/mL, which overlaps with the range of claims 14 & 20, and encompasses ranges of claims 15, 16, 21, 22, rendering the ranges of these claims prima facie obvious from the overlapping range, or from within the prior art range (MPEP 2144.05 (I)), and also, alternatively, as a result of routine optimization of prior art amounts (MPEP 2144.05 (II)(A)).
Regarding the arguments of Garwood, the concentrations of glycerol are widely ranging, with boundaries being set by considerations set forth. Additionally, it is noted that Ezealisiji also names glycerin (a.k.a., glycerol) as a common cosolvent (472, 2nd paragraph). Considering concentrations of cosolvents taught in Table 1, the range tested includes 30-50 %, a subset of claim 14 and this range also encompasses ranges of claim 15, and 16, rendering these amounts obvious for glycerol, based on the solubility tests of Ezealisiji.
Regarding arguments about individual references, such as Wockhardt, removal of ethanol from Laroxyl 40 is reliant on the teachings of EMA, which clearly teaches ethanol should not be included, but surfactant/emulsifier can be used to replace the ethanol function.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIMOTHY P THOMAS whose telephone number is (571)272-8994. The examiner can normally be reached M-Th 6:30-5:00.
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TIMOTHY P. THOMAS
Primary Examiner
Art Unit 1614
/TIMOTHY P THOMAS/Primary Examiner, Art Unit 1614