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 .
DETAILED ACTION
Status of claims
The amendment filed on August 15, 2025 is acknowledged. Claims 1-20 and 32-34 have been canceled. Claims 21-31 are under examination in the instant office action.
Applicants' arguments, filed on August 15, 2025, have been fully considered but they are not deemed to be persuasive. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied in view of amendments. They constitute the complete set presently being applied to the instant application. Responses are limited to Applicants' arguments relevant to either reiterated or newly applied rejections.
Claim Rejections - 35 USC § 112 (b)
The following is a quotation of 35 U.S.C. 112(b):
(B) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 21-31 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention. All the dependent claims are included.
Claim 1 as amended recites “the subject” in line 15. There is a lack of antecedent base for this limitation. Amending it to “the patient” would obviate the rejection.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, 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.
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 21-31 are rejected under 35 U.S.C. 103 as being unpatentable over Presentation of Dr. Matthias Unterhuber (“La Caffeina nelle sincopi vasovagali”, Malabo project, Tiguillio Cardiologia, April 7-8, 2016, 57 pages) in view of Strieper et al. (JACC 22 (2):594-7m Aug. 1993) and US 2009/0280160 (hereafter, Monteith). All references are cited in IDS filed on 11/12/2024.
The presentation of Dr. Matthias Unterhuber discloses the use of 100 mg (if weight <60kg) or 200 mg (if weight is >60 kg) of caffeine with capsaicin for syncope (procedure, Flowchart, limitation, and conclusion slides).
The presentation of Dr. Matthias Unterhuber further discloses that caffeine with capsaicin is prepared in a sublingual spray solution. The presentation of Dr. Matthias Unterhuber specifically discloses a composition comprising 200 mg caffeine, 0.1 mg capsaicin, and 1 ml alcohol (carrier) for sublingual administration in the treatment of syncope (see slides, especially Malabo-project and preparation slides). The dose amount of capsaicin falls within the ranges recited in claim 22 as amended. The dose amount of caffeine falls within the ranges recited in claim 23. Alcohol is an aqueous carrier as recited in the instant claim 26.
The presentation of Dr. Matthias Unterhuber teaches that caffeine and capsaicin are able to increase blood pressure and heart rate in order to avoid of a loss of consciousness in affected patient’s recurrent vasovagal syncope (Malabo-project slide).
The presentation of Dr. Matthias Unterhuber does not specifically disclose the addition of an effective amount per dose of an α-agonist such as phenylephrine or etilefrine and a dose thereof.
Strieper et al. teach the efficacy of alpha-adrenergic agonists such as phenylephrine for treating or preventing pediatric neurocardiogenic syncope (abstract). Strieper et al. further teach that alpha-adrenergic agonists prevent neurocardiogenic syncope by one or two mechanisms as follows: first, through venoconstriction, alpha-agonists may lessen venous capacitance, thereby preventing venodilation and venous pooling with its resultant decrease in preload and second, systemic hypotension may be blocked by alpha-agonist arteriolar vasoconstriction, causing an increase in systemic vascular resistance (p597, Conclusion).
Monteith discloses a pharmaceutical composition suitable for sublingual systemic administration of phenylephrine or a pharmaceutically acceptable salt thereof, wherein the composition allows for systemic absorption of phenylephrine from the floor of the mouth. (abstract, [0010], and [0016]). Monteith further discloses the sublingual mucosa is comparatively more permeable and rapid absorption leads to acceptable bioavailabilities of many drugs, and is convenient, accessible, and generally well accepted and administration of phenylephrine to these regions of the oral mucosa will allow for similar systemic uptake of parenteral phenylephrine ([0034]). Monteith further discloses that suitable semi-solid forms include gels and hydrogel system (aqueous gel) ([0040]). Monteith also discloses the single dosage results in peak concentration of unmetabolized phenylephrine in plasma of the subject at a time point of from about 0.1 and about 1.5 hours after the composition contacts the oral mucosa ([0062]). Monteith specifically discloses a sublingual dosage form comprising 5-20 mg of phenylephrine HCl, particularly 10 mg of phenylephrine HCl ([0137]-[0139] and Table 6-7). The dose falls within the range recited in claim 1 as amended. In addition, Monteith teaches that the composition of the invention provides a therapeutically effective phenylephrine dose for a period of time after a single dose is administered to a subject who is an animal, human or otherwise, in need of treatment with phenylephrine ([0061]). Monteith further discloses a drug delivery device adapted for application sublingually of the oral cavity for fast release thereon of a composition comprising phenylephrine or a pharmaceutically acceptable salt thereof, said device comprising a body (reservoir) having the composition distributed therein and having a size and shape suitable for sublingual application ([0016]). Liquid forms can be those suitable for spraying from a pump spray or pressurized spray device such as an aerosol spray ([0038]) and the composition is in the form for application by means of a spray, mousse or drench (claim 42).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the composition comprising caffeine and capsaicin in combination with α-agonist such as phenylephrine for treating syncope because both the composition comprising caffeine and capsaicin and α-agonist such as phenylephrine are taught to be effective for treating syncope and they can be administered in sublingual formulations. According to M.P.E.P. § 2144.06, “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). In this case, the skilled artisan would have been motivated to combine the composition comprising caffeine and capsaicin with phenylephrine based on their independent efficacy in treating the same condition (i.e., syncope). The skilled artisan would have a reasonable expectation of success of getting combined effects on treating syncope.
As to the dose of phenylephrine, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention optimize the dose amounts of phenylephrine for obtaining the best therapeutic effects. Monteith disclose dosing ranges overlapping or close to those claimed, thus a person of ordinary skill in the art can easily determine an appropriate dose to administer to a subject without undue experimentation. Typically, a physician will determine the actual dosage which will be most suitable for an individual patient and it will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy. In addition, it is well-established that merely selecting proportions and ranges is not patentable absent a showing of criticality. In re Becket, 33 USPQ 33; In re Russell, 169 USPQ 426. “[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); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”)
As to gelling agents such as polyethylene glycol and polyvinylpyrrolidone recited in claim 27-28, the term “gelling agent” in the claim simply states an inherent property of polyethylene glycol and polyvinylpyrrolidone. Note that the claim language does not require any particular amount of the gelling agent, as long as it is present. Monteith discloses that the compositions comprise at least one or a combination of biodegradable polymers to form a matrix with the phenylephrine or pharmaceutically acceptable salt thereof such that the matrix would provide an instant phenylephrine release upon contact with oral mucous without taking any water and the matrix can be in the form of a film or lattice comprising the biodegradable polymers such as polyvinylpyrrolidine and polyethylene glycol ([0055] and claim 31). Monteith further discloses the use of polyethylene glycol as hydrophilic agent and specifically discloses a composition comprising phenylephrine, PEG 400 and water ([0047], claims 27 and 30-31[0133] and Table 3). Thus, it would have been prima facie obvious to one of ordinary skill in the art to further add polyethylene glycol such as PEG 400 or polyvinylpyrrolidone to the composition comprising caffeine and capsaicin with phenylephrine because those have been taught to be suitable carrier material for preparing a sublingual formulation by Monteith. One of ordinary skill in the art would have been motivated to do so on the reasonable expectation that such addition would provide an alternative formulation suitable for sublingual administration as evidenced by Monteith.
As to aqueous gel formulation recited in claim 30, it would have been prima facie obvious to one of ordinary skill in the art to prepare the composition comprising caffeine and capsaicin with phenylephrine in an aqueous gel because an aqueous gel (hydrogel) was known to be a suitable dosage form for sublingual administration of phenylephrine which allows for rapid systemic absorption as evidenced by Monteith. Since the composition comprising caffeine and capsaicin and phenylephrine were known to be suitable for sublingual administration as evidenced by the presentation of Dr. Matthias and Monteith, one of ordinary skill in the art would have been motivated to prepare any suitable alternative formulations including an aqueous gel formulation disclosed in Monteith for sublingual administration on the reasonable expectation that resulting formulations would provide similar effects.
As to flavoring agent, stabilizing agent or coloring agent recited in claim 31, it would have been prima facie obvious to one of ordinary skill in the art to add those agents to the composition comprising caffeine and capsaicin with phenylephrine for improving taste or appearance of the formulation or enhancing the stability of the composition. In addition, Monteith discloses the addition of flavors and colorants ([0144]). Generally, it is prima facie obvious to select a known material for incorporation into a composition based on its recognized suitability for its intended use. See MPEP 2144.07.
Response to Applicant’s arguments
First, Applicants argued that claims have been amended to recite that the dose of alpha-agonist, capsaicin and caffeine are combined into a single formulation for simultaneous administration. However, the claim 1 as amended does not recite “the dose of alpha-agonist, capsaicin and caffeine are combined into a single formulation”, but only recite “formulated for simultaneous administration”. It should be noted that drugs can be administered simultaneously without combining them in a single formulation.
Second, in response to applicant's arguments against the references individually, 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). It is important to note that in an obvious rejection, it is not necessary that one reference addresses any limitation in a particular claim but that the references, when combined, do so.
In this case, the presentation of Dr. Matthias Unterhuber already teaches the use of the combination of caffeine and capsaicin in the same effective amounts in the same sublingual formulation for treating syncope. While the presentation of Dr. Matthias does not teach the addition of alpha-agonist such as phenylephrine, it was well known in the art that phenylephrine as alpha-adrenergic agonist is effective for treating or preventing syncope through vasoconstriction and preventing venodilation a evidenced by Strieper et al. and can be used in a sublingual formulation for more permeable and rapid absorption which allow for similar systemic uptake of parenteral phenylephrine a evidenced by Monteith. According to M.P.E.P. § 2144.06, “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). In this case, one would be motivated to use phenylephrine with the combination of caffeine and capsaicin taught by the presentation of Dr. Matthias Unterhuber based on their independent efficacy in treating syncope. One would have a reasonable expectation of success, as noted above, that two independently successful treatments would be similarly successful when combined. In addition, it would have been obvious to administer them simultaneously in a sublingual formulation for combined effects and patients’ convenience as both are taught to be suitable for sublingual administration.
It should be noted that addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 “need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR v. Teleflex, 127 S.Ct. 1727, 1741 (2007). The Court emphasized that “[a] person of ordinary skill is... a person of ordinary creativity, not an automaton.” Id. at 1742. The examiner recognizes that obviousness can only be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988) and In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). It is also noted that "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)).
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 extension fee 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 date of this final action.
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/BONG-SOOK BAEK/Primary Examiner, Art Unit 1611