DETAILED ACTION
The receipt is acknowledged of applicant’s amendment and request for continued examination (RCE) filed 03/16/2026.
Claims 20, 22-27 are pending and subject of this office 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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/16/2026 has been entered.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)
The disclosure of the prior-filed application, Applications No. 14/32,561 and 15/818,056, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
There is not adequate support for multiple limitations recited in the instant claims in the previously filed applications. For example, application No. 14/32,561 does not disclose epinephrine instantly claimed by the present application. Applicant first disclosed epinephrine in application 15/818,056. Further, the instantly claimed steps of the claimed method was first disclosed in the instant application, in particular step of “providing including dispensing said first dosage and said second dosage of said at least one sublingual 1-epinephrine formulation from an at least one dispensing container and placing said first dosage and said second dosage of said at least one sublingual 1-epinephrine formulation under said human patient's tongue; and having said human patient hold said tongue down over said first dosage and said second dosage of said at least one sublingual 1-epinephrine formulation, while keeping said tongue still to protect said first dosage and said second dosage of said at least one sublingual 1-epinephrine formulation from mixing with saliva above said tongue, and not swallowing any saliva for over one minute.” No support for the newly cited claims 21-27 in any of the parent applications.
Thus, Applicant does not have sufficient support in the parent application 14/323,561 to earn the priority date of the instantly claimed epinephrine, and no sufficient support in the parent applications 14/323,561 and 15/818,056 for the claimed method steps.
Accordingly, the filing date of the present application, which is 09/13/2018, will be considered for examining instant claimed method and steps of the method, and the filing date application 15/818,056 which is 11/20/2017 will be considered in examining epinephrine.
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 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 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 20, 22-27 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Hill et al. (US 2007/0293582, of record), Carver et al. (US 2010/00291160, of record), the article by the article by Rawas-Qalaji et al. (“Fast-disintegrating sublingual tablets: Effect of epinephrine load on tablet characteristics”, of record), Gu et. al. (“Is epinephrine administration by sublingual tablet feasible for the first-aid treatment of anaphylaxis” A proof-of-concept study”, IDS filed 10/24/2018), the article by Simons et al. (“Fast disintegrating Sublingual Epinephrine Tablets: Effect of Tablet Dimensions on Tablet Characteristics” of record), the article by Brahmbhatt et al. (“Formulation and Evaluation of Sublingual Tablet For Naratr” of record), the article by Strain et al. (“Relative Bioavailability of Different Buprenorphine Formulations Under Chronic Dosing Conditions” of record), Monteith et al. (US 2009/0280160, of record), and the article by Raja (“Formulation and evaluation of orally disintegrating tablets of taste masked drug” of record).
Applicant Claims
Claim 20 is directed to a method of transmucosal delivery of epinephrine to a human patient, the method comprising:
providing the patient with a first solid dosage of a sublingual I-epinephrine formulation under the patient’s tongue;
waiting a period of at least 5 minutes while the patient holds the tongue down and still over said first solid dosage and refrains from disturbing and mixing the solid dosage with saliva and from swallowing saliva mixed with the solid dosage;
providing the patient with a second solid dosage of the sublingual l-epinephrine formulation under the patient’s tongue;
waiting for the first and second solid dosages to dissolve, while the patient holds the tongue down and still over said first and second solid dosages and refrains from disturbing and mixing the solid dosages with saliva and from swallowing saliva any saliva mixed with the solid dosage;
waiting for about three to about five minutes before ingesting or rinsing away said saliva; and thereby elevating the patient’s plasma epinephrine levels, and maintaining at least one of the patient’s blood pressure, pulse, and breathing rate,
wherein the first and second solid dosages are dispensed from a dispensing container to under the patient's tongue;
wherein when each solid dosage comprises 2.5 mg or 5 mg epinephrine and the first and second solid dosages are provided about five minutes apart, the method maintains elevated plasma epinephrine concentrations up to 20 pg/mL for up to six hours, and achieves more steady plasma epinephrine concentrations for up to six hours than intramuscular administration;
wherein when each solid dosage comprises 35 mg or 40 mg epinephrine and the first and second solid dosages are provided about five minutes apart, the method maintains plasma epinephrine concentrations above 40 pg/mL for about four to six hours; and
wherein each solid dosage form comprises the 2.5 mg, 5 mg, 35 mg, or 40 mg epinephrine, microcrystalline cellulose at 35% w/w, crospovidone at 5% w/w, sucralose at 0.34% w/w, magnesium stearate at 1% w/w, and mannitol to 100% w/w.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Hill teaches sublingual dosing regimen for administering a series of epinephrine doses for treatment of allergic emergencies (abstract). Hill teaches treating an allergic emergency and anaphylaxis in a patient comprising the steps of (a) administering to the patient two doses of sublingual dosage form comprising epinephrine; and (b) administering to the patient a first dose of an injectable dosage form comprising epinephrine. A third dose of sublingual epinephrine can be administered. The reference teaches kit comprising multiple sublingual doses (¶¶ 0012, 0013, 0095, 0121; examples 4-10). The sublingual dosages are tablets, i.e. solid (¶¶ 0021, 0043-0045, 0060-0064; claims 25 and 26). The time between the administrations is 3-10 minutes, or 5 minutes (¶¶ 0029, 0111, 0120; examples). The examples teach the first sublingual dosage form of epinephrine is administered under the tongue and is maintained under the tongue until fully dissolved as soon as the patient begins experience symptoms of anaphylaxis, and if the symptoms of anaphylaxis do not improve or terminate within about 5 minutes, the second sublingual dosage form is administered under the tongue and is maintained under the tongue until fully dissolved, and if the symptoms of anaphylaxis do not improve or terminate within about 5 minutes, the injectable dosage form is administered (¶ 0151). Hill teaches the sublingual dosage is administered to the patient by another person, such as parent, guardian, a care giver, or health care professional. Administration by health care professional such as in an emergency sitting, such as in the field, including ambulance or at a patient’s home (¶ 0026). The dosage of sublingual epinephrine is from 1 mg to 100 mg (¶ 0051). Each administered sublingual dosage form and subsequent dosage form comprises amount of epinephrine bioequivalent to 0.1-0.5 mg administered intramuscularly (¶¶ 0019-0020). The sublingual dosage form comprises mannitol, microcrystalline cellulose (Avicel®), crospovidone, sucralose, and magnesium stearate (¶¶ 0051, 0053, 0055-0058).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
While Hill teaches to maintain the sublingual dosage forms under the tongue until fully dissolved, which implies keeping the tongue still to protect sublingual epinephrine dosages from mixing with saliva above said tongue, and not ingesting any of the drug or saliva, however the reference does not explicitly teach the step of keeping the tongue still to refrain the from disturbing the dosage form to protect the dosage form from mixing with saliva and not ingesting any saliva as instantly claimed by claim 20.
The reference does not teach rinsing away saliva after about 3-5 minutes as claimed by claim 20.
While Hill teaches the dosage of sublingual epinephrine is from 1-100 mg and teaches it is repeated, the reference does not explicitly teach the method achieves more stable plasma epinephrine concentrations for up to three hours than does administration of intramuscular epinephrine as claimed by claim 20.
While Hill teaches the ingredients of the sublingual formulation as claimed by claim 20, the reference does not teach the amount of each ingredients as claimed.
Carver teaches non-invasive drug delivery systems useful for the absorption of therapeutically active agents through the epithelial membrane (abstract). Non-invasive delivery includes sublingual-type formulations that are more effective than simply chewing, i.e. ingesting, and swallowing because drug efficiently pass through the sublingual membrane and into the blood without irreversible modification (¶¶ 0009, 0061). Example of drugs to be delivered sublingually is epinephrine (¶¶ 0082, 0092). The reference teaches sublingual formulation should not be swallowed or chewed, i.e. not ingested, and patient instructed towards non-invasive sublingual delivery rather than ingestion of the formulation, and the formulation allowed to dissolve in the mouth (¶¶ 0110, 0111, 0128). Example 6 teaches epinephrine tablet is administered to a patient as a sublingual (under the tongue) dose that is allowed to dissolve in the mouth over a period of 1 second to three minutes with a minimal residence time of 30 to 90 seconds under the tongue (¶ 0151). The formulation can be protected and prevented from chewing and swallowing (¶¶ 0072, 0100, 0105, 0106, 0110, 0111). The formulation can be encapsulated or having protective coating (¶¶ 0123, 0127, 0150), i.e. barrier to protect the formulation from mixing with the saliva. The formulation is prevented from easily dislodging from its intended absorption area by including materials to enhance stickiness and bioadhesion of the formulation and may contain adhesive (¶¶ 0107-0109, 0118, 0124), i.e. adhered to the site of application. Adhesive also reads on barrier.
Rawas-Qalaji teaches increasing epinephrine load in sublingual tablet will increase disintegration time of the tablet. The reference teaches 2 minutes disintegration is specified as acceptable (see the entire document, and in particular E4, left column).
Gu teaches administering epinephrine dose sublingually, and holding the dose under the tongue for 5 minutes to prevent it from being chewed or swallowed, and before releasing the tongue, the dose is rinsed by water to release the dose. Such a method of epinephrine administration is a practical alternative to injection of epinephrine, and provides rapid improvement of plasma concentration of epinephrine and rapid decrease in chemical mediator causing allergy than injectable dose (see the entire document, and in particular: abstract; page 214, right column; discussion).
Simon teaches while epinephrine is the drug of choice for emergency treatment of anaphylaxis, it is extremely metabolized after oral administration by enzymes in gastrointestinal tract and liver, and absorbed rapidly sublingually by fast disintegrating tablets from sublingual blood vessels (page 524, right column).
Brahmbhatt defines sublingual tablets are the one that dissolves when held beneath the tongue, permitting direct absorption of active ingredients by the oral mucosa lining the mouth under the tongue to produce immediate systemic effect (see page 19, first paragraph of the introduction).
Strain teaches that when sublingual tablet is administered to subjects, the subjects are instructed to hold tablets under tongue till tablet completely dissolved, and for solution it is held under the tongue for at least 5 minutes, i.e. not ingested (see page 39, left column, paragraph 2.5).
Monteith teaches sublingual formulation to administer drugs to the floor of the mouth and adheres to the mucosal surface and allows for systemic absorption, thus optimizes the systemic exposure and by-passes presystemic metabolism (¶¶ 0009-0017, 0030). The formulation is solid (¶ 0037). The formulation provide sustained release of the drug from 5 minutes and up to 24 hours and cumulative plasma concentration (¶¶ 0036, 0050). The formulation comprises 1-30% drug, 30-60% mannitol, 5-20% crospovidone, 2-20% microcrystalline cellulose (Avicel PH 101), 1% magnesium stearate, and 0.1-1 sucralose (¶¶0132, 0134).
Raja teaches that the sublingual dosage form held under the tongue and allowed to be actively moved in the oral cavity, disintegrates faster than dosage form disintegrates without further encouragement (paragraph bridging pages 16 and 17).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP §2142-2143)
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the present invention to treat allergic emergencies in a patient using first and second sublingual epinephrine dosage forms that are maintained under the tongue until completely dissolved as taught by Hill, and instruct patient to hold the sublingual dose of epinephrine under the tongue till it dissolve, rather than ingesting the dosage form of epinephrine, as taught by Carver and further instruct the patient to hold the sublingual dosage form for at least 2 minutes as taught by Rawas-Qalaji. One would have been motivated to do so because Carver teaches this method is non-invasive and more effective than simply ingesting the drug because drug efficiently pass through the sublingual membrane and into the blood without irreversible modification, and because Rawas-Qalaji teaches 2 minutes is the acceptable time for disintegration of epinephrine sublingual tablet. One would reasonably expect successfully treating allergic emergency using sublingual administration of first and second epinephrine dosage forms that are held under the tongue for at least 2 minutes, and not ingested as a first aid treatment to achieve high tissue and plasma concentrations without irreversible modification.
One having ordinary skill in the art would have rinsed the sublingual dose taught by the combination of Hill, Carver, and Rawas-Qalaji after holding it under the tongue during treatment time up to 5 minutes as taught by Gu because Gu teaches such a method ensures that the dosage form is not chewed or swallowed, and rinsed to stop the epinephrine release when it is not further needed, and such a method of epinephrine administration is a practical alternative to injection of epinephrine, and provides rapid improvement of plasma concentration of epinephrine and rapid decrease in chemical mediator causing allergy than injectable dose.
Further, one having ordinary skill in the art would have instruct the patient not ingest the sublingual dose of epinephrine and hold it under the tongue as taught by Simon, Brahmbhatt and Strain, even after dissolution, because Simon teaches that epinephrine is extremely metabolized after oral administration by enzymes in gastrointestinal tract and liver while sublingual epinephrine is absorbed rapidly by fast disintegrating tablets from sublingual blood vessels, and Brahmbhatt teaches that sublingual tablet dissolves when held beneath the tongue, permitting direct absorption of active ingredients by the oral mucosa lining the mouth under the tongue to produce immediate systemic effect, and because Strain teaches that when sublingual tablet is administered to subjects, the subjects are instructed to hold tablets under tongue till tablet completely dissolved, and for solution it is held under the tongue for at least 5 minutes. One would reasonably expect holding the sublingual dose under the tongue without ingestion to permit rapid action and relief of the allergic emergency condition and to avoid wasting of the dose by ingestion and metabolism of epinephrine by gastrointestinal and liver enzymes.
Furthermore, one having ordinary skill in the art before the effective filing date of the present invention would have formulate the sublingual formulation comprising mannitol, microcrystalline cellulose (Avicel®), crospovidone, sucralose, and magnesium stearate as taught by Hill, and use the amount taught by Monteith of 30-60% mannitol, 5-20% crospovidone, 2-20% microcrystalline cellulose (Avicel PH 101), 1% magnesium stearate, and 0.1-1 sucralose because Monteith teaches formulation comprising such amounts is suitable for sublingual solid dosage form to be administered to the floor of the mouth and to adhere to the mucosal surface and to allow for systemic absorption, thus optimizes the systemic exposure and by-passes presystemic metabolism.
One having ordinary skill in the art would hold the dosage form under the tongue without moving it the oral cavity to achieve slower disintegration for longer time as taught by Raja and consequently longer maintenance of the plasma concentration.
Regarding waiting for at least 5 minutes and holding the dosage form after it dissolve for three to five minutes as claimed by claim 20, Rawas-Qalaji teaches the disintegration time of sublingual epinephrine tablet is 2 minutes, and Strain teaches holding the dosage form for at least 5 minutes under the tongue when it is liquid, i.e. dissolved dosage form. Further, if the dosage form is swallowed immediately after dissolution this means it is ingested, which the cited references are trying to avoid. The references imply delaying swallowing the dosage form after dissolution to allow absorption by the sublingual mucosa.
Regarding the limitation of rinsing the dosage form after about 5 minutes, this is taught by Gu.
Regarding the claimed plasma concentrations and the limitation that “the method achieves more steady plasma epinephrine concentrations for at least three hours than does administration of intramuscular epinephrine” as claimed by claim 20, this expected from combination of the cited references that teaches repeated doses that will extend the delivery to the desired time that can reach up to 6 hours, till the patient recovers. The prior art teaches the claimed ingredients of the dosage form, and the claimed plasma concentration is expected from the prior art formulation. Further Raja teaches longer holding of the sublingual dosage form provides slower disintegration, implying longer period of effective plasma concentration.
One having ordinary skill in the art would have administered epinephrine sublingually as taught by the above references, and expected it to provide plasma concentrations superior to the intramuscular administration as taught by Hill because Hill teaches each administered sublingual dosage form and subsequent sublingual dosage form comprises amount of epinephrine bioequivalent to 0.1-0.5 mg administered intramuscularly, and this sublingual dosage form taught by Hill comprises1-100 mg that embraces the claimed amounts of 2.5 mg or 5 mg. Hill teaches such sublingual dosage forms provide relief of anaphylaxis and can be repeated till the anaphylaxis attack subsides. This implies that plasma level of epinephrine stayed steady with the repeated administration for the required period of time to achieve the desired effect. Gu teaches sublingual epinephrine provide higher plasma concentration than injection of epinephrine.
Regarding steady plasma epinephrine concentration as claimed by claim 20, it is noted that combination of the cited references teaches epinephrine dose used by applicant and are expected to have stable plasma concentration for the same period based on how many times the dose is repeated. Plasma concentration depends on pharmacokinetic of the drug and on the formulation of the sublingual formulation. Note that applicant does not claim any specific number of repeating the dose, or formulation that provide steady plasma concentration. Applicant claim 2.5 and 5 mg sublingual dosage that is administered for at least 2 times, to provide the same plasma concentration as injectable dose for longer time, which is taught by Hill.
Regarding solid dosage forms claimed by claim 20, all the cited references teaches solid tablets.
Regarding the dose of 2.5 to 5 mg in each dosage form as claimed by claim 20, Hill teaches 1-100 mg in each dosage form that embraces the claimed dose. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05 [R-5]. One having ordinary skill in the art would have determined each dose based on patients age, weight, severity of the anaphylaxis, etc.
Regarding the amount of different ingredients of the sublingual dosage form as claimed by claim 20, the prior art teaches the claimed ingredients of the dosage form in amounts overlapping with the claimed amount. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05 [R-5]. One having ordinary skill in the art would have determined the amount of each ingredients to achieve the desired consistency and absorbency of the formulation.
Regarding claim 20 that the first dosage and the second dosage are provided at least five minutes apart, this is taught by Hill that teaches 3-10 minutes, and 5 minutes.
Regarding anaphylaxis claimed by claim 22, Hill and Simon teach anaphylaxis treated by administering sublingual epinephrine.
Regarding claim 23 that the method is performed when injectable liquid epinephrine formulation is not available or is not possible, Hill teaches sublingual epinephrine is administered by another person such as care giver or health professional such as in an emergency sitting, such as in the field, including ambulance or at a patient’s home, this implies injection is not available at patient’s home. It is obvious to start any available anti-anaphylaxis dosage form such as sublingual epinephrine if injection not available.
Regarding claim 24 that the method is performed until emergency medical services arrive to treat or transport said human patient, it is obvious to use the sublingual epinephrine when available and not to remain without treatment waiting for emergency medical service. Further, the teachings of Hill imply that the sublingual dose of epinephrine is administered first before any injection that is usually administered in hospitals.
Regarding claim 25 that patient is a soldier on a battlefield or in a location without emergency medical services, Hill is generic in term of the patient, and this embrace any patient susceptible to anaphylaxis wherein medical service is not readily available such as soldiers in the battlefield. Hill further teaches patient is the field such as home that is logically a location without medical service.
Regarding claim 26 that sublingual administration is followed by subsequent step of administering an at least one injection of an injectable epinephrine formulation, this is taught and exemplified by Hill.
Regarding claim 27 that providing a third dosage of the at least one sublingual epinephrine formulation, Hill teaches a third sublingual epinephrine dosage form.
Absent any evidence to the contrary, and based upon the teachings of the prior art, there would have been a reasonable expectation of success in practicing the instantly claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention.
Response to Arguments
Applicant's arguments filed 03/16/2026 have been fully considered but they are not persuasive.
Priority
The examiner acknowledged applicant’s statement that: “Applicants do not
acquiescence to or agree with the Examiner's position, but respond below to the Examiner’s rejections in order to advance prosecution of the present application.”
Rejections under 35 U.S.C. § 103
Applicant argues that the PTO has not established a prima facie case of obviousness against currently amended independent claim 20 because the PTO has not demonstrated, at a minimum, that the cited references teach or suggest each and every limitation of claim 20. The PTO has not demonstrated that the cited references teach or suggest a method of transmucosal delivery of epinephrine to a human patient comprising the claimed sequence of steps.
In response to this argument, the examiner respectfully disagree with applicant because prima facie case of obviousness has been established because all the steps and limitations of the claimed method are taught by combination of the cited references. Motivation to combine the references exists, as well as reasonable expectation of successfully achieve the present invention. The obviousness does not require absolute predictability of success all that is required is a reasonable expectation of success. See In re Kubin, 561 F.3d at 1360. The Court has held that "the test of obviousness is not express suggestion of the claimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them." See In re Rosselet, 146 USPQ 183, 186 (CCPA 1965). "There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art." Motorola, Inc. v. Interdigital Tech. Corp., 43 USPQ2d 1481, 1489 (Fed. Cir.1997). An obviousness determination is not the result of a rigid formula disassociated from the consideration of the facts of a case. Indeed, the common sense of those skilled in the art demonstrates why some combinations would have been obvious where others would not. See KSR Int'l Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) ("The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.").
Regarding the sequence of steps of the claimed method, it is noted that the expression “comprising” of the claims language permits any sequence or order of the steps of the claimed method. It has been held that it is prima facie obvious to reverse the order of the prior art process steps, Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946), selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results; In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930). Applicant’s does not require certain order, and applicant failed to show superior and unexpected results obtained from the claimed step order.
Applicant argues that the claimed method demonstrates results that could not have been predicted from the disclosures of the cited references. For example, as set forth in the claim and demonstrated in the Application, when each solid dosage comprises 2.5 mg or 5 mg epinephrine and the first and second solid dosages are provided about five minutes apart, the method maintains elevated plasma epinephrine concentrations up to 20 pg/mL for up to six hours, and achieves more steady plasma epinephrine concentrations for up to six hours than intramuscular administration of epinephrine. PTO has failed to show that the cited references teach or suggest the particular sequence of steps required by the claimed method and accordingly fails to establish that the results of the method could be expected in view of the references.
In response to this argument, it is argued that the results applicant achieved are expected from the prior art formulation that has the claimed formulation and administered by the claimed method as set forth in this office action. Hill teaches sublingual epinephrine tablet for treating anaphylaxis that can be repeated till help arrives, including 2 times or more. Note the “comprising” language of the claims permits any sequence of steps. Hill teaches bioequivalency between sublingual dosage form comprising amount embracing the claimed amount and intramuscular injection. Sublingual dose can be repeated till patient recovers or help arrives, that implies it can be extended to hours. Holding the dosage form under the tongue, as taught by Raja, expected to provide slower disintegration and consequently longer duration of action and longer maintenance of the plasma concentration. Therefore, the prior art teaches the claimed method using the claimed dosage form, and any properties applicant achieved is expected from the method taught by combination of the cited references, absent evidence to the contrary. Therefore, unexpected superior results in the instant specification are not unexpected results and therefore cannot rebut prima facie obviousness. The examiner directs applicant's attention to MPEP 716.02 (a). "A greater than expected result is an evidentiary factor pertinent to the legal conclusion of
obviousness...of the claims at issue." In re Corkhill, 711 F.2d 1496, 266 USPQ 1006
(Fed.Cir. 1985). In Corkhill, the claimed combination showed an additive result when a
diminished result would have been expected. Furthermore, the MPEP states, "Expected
beneficial results are evidence of obviousness of a claimed invention, just as
unexpected results are evidence of nonobviousness thereof." In re Gershon, 372 F.2d
535, 538, 152 USPQ 602, 604 (CCPA 1967).
Applicant disagrees with the PTO position that the cited references make obvious the results applicant achieved are expected from the prior art formulation that has the claimed formulation and administered by the claimed method". Office Action, pg. 18. Applicant submits that this conclusion is both premature and unfounded, because the PTO has not demonstrated that the prior art in fact teaches or suggests every feature of the claimed method.
In response to this argument, the examiner maintains that combination of the cited references teaches all the elements of the claimed method including the steps and ingredients of the claimed dosage form. It is expected that the method and dosage form produced the combination of the cited references to extend the delivery of epinephrine by repeating the administration of the sublingual dose to the desired time, absent evidence to the contrary. The delivery of epinephrine from a sublingual dose of the prior art can reach up to 6 hours or more till the patient recovers or help arrives. Applicant claiming 2.5 and 5 mg sublingual dosage that is administered for 2 times, to provide the same plasma concentration as injectable dose for longer time, as suggested by Hill. All the limitations of the claimed method including steps and ingredients are taught by combination of the cited references. Obviousness does not require absolute predictability of success all that is required is a reasonable expectation of success. See In re Kubin, 561 F.3d at 1360. The Court has held that "the test of obviousness is not express suggestion of the claimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them." See In re Rosselet, 146 USPQ 183, 186 (CCPA 1965). "There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art." Motorola, Inc. V. Interdigital Tech. Corp., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997). An obviousness determination is not the result of a rigid formula disassociated from the consideration of the facts of a case. Indeed, the common sense of those skilled in the art demonstrates why some combinations would have been obvious where others would not. See KSR Int'l Co. V. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) ("The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.").
Applicant argues that the PTO cites Hill for teaching a sublingual epinephrine dosing regimen in which plural doses are administered consecutively. Indeed, the PTO accurately describes Hill as teaching that "a first sublingual dosage form of epinephrine is administered under the tongue and is maintained under the tongue until fully dissolved followed by administration of a second sublingual dosage form. Office Action, pg. 6 (emphasis in original). However, the claimed method clearly sets forth a semi-consecutive dosing regimen in which a second solid dosage is administered while the first solid dosage-present in a disintegrated state-is still being held under the subject's tongue. This is different from mere consecutive dosing as taught in Hill, and a skilled person would understand that the absorption kinetics and resulting plasma concentration curve would differ for the two approaches.
In response to this argument, applicant’s attention is directed to the scope of the present claims that recites: “providing first dose,….providing second dose, ….waiting for the first and second dose to dissolve….”. the claims do not require second solid dosage is administered while the first solid dosage-present in a disintegrated state-is still being held under the subject's tongue. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., a second solid dosage is administered while the first solid dosage-present in a disintegrated state-is still being held under the subject's tongue) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Further, it is noted that applicant argues against Hill reference individually while obviousness is based on combination of references. One cannot show non-obviousness by attacking the references individually while obviousness is based on combination of references.
Applicant argues that the PTO suggests that Hill's use of repeated dosing "implies that plasma level of epinephrine stayed steady for the required time to achieve the desired effect." Office Action, pg. 13. Applicant submits that the stated "desired effect" of said repeated dosing in Hill is to treat the symptoms of anaphylaxis until the underlying reaction terminates. However, even if the Hill method is assumed to accomplish such a result, that does not necessarily imply achievement of a steady plasma level (as opposed to, e.g., a repeating cycle of spikes and declines in plasma level). Applicant submits that it certainly does not necessarily imply the particular pharmacokinetics required by the claims-particularly where the prior art method and the claimed method are different.
In response to this argument, it is argued that Hill teaches bioequivalency between sublingual dosage form comprising amount embracing the claimed amount and intramuscular injection. Sublingual dose can be repeated till patient recovers or help arrives, that implies it can be extended to hours. Holding the dosage form under the tongue, as taught by Gu and Raja, expected to provide slower disintegration and consequently longer duration of action and longer maintenance of the plasma concentration. Therefore, the prior art teaches the claimed method using the claimed dosage form, and any properties applicant achieved is expected from the method taught by combination of the cited references, absent evidence to the contrary. Combination of the cited references suggests continuous administration that suggest steady plasma level, e.g. Figure 1 of Gu reference. The formulation itself is responsible for release of the active agent from the formulation. The claimed formulation is taught by Monteith and taught to provide sustained release of the drug from 5 minutes and up to 24 hours and cumulative plasma concentration. Therefore, combination of the cited references suggests a steady plasma level. Further, one having ordinary skill in the art would hold the dosage form under the tongue without moving it the oral cavity to achieve slower disintegration for longer time as taught by Raja and consequently longer maintenance of the plasma concentration. Furthermore, relief of anaphylaxis implies that plasma level of epinephrine stayed steady with the repeated administration for the required period of time to achieve the desired effect. It is expected that the method and dosage form produced the combination of the cited references to extend the delivery of epinephrine by repeating the administration of the sublingual dose to the desired time that can reach up to 6 hours or more till the patient recovers or help arrives. Applicant claiming 2.5 and 5 mg sublingual dosage that is administered for 2 times, to provide the same plasma concentration as injectable dose for longer time, as suggested by Hill. The claimed method and formulation are taught by Hill and the amounts of ingredients in the formulation are taught by Monteith.
According to MPEP 2112.02, products of identical chemical composition cannot have mutually exclusive properties. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches an identical preparation, the properties applicant discloses and/or claims are necessarily present. Furthermore, since the examiner does not possess access to laboratory equipment, burden shifts to applicant to show unexpected results by declaration or otherwise as In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980). When the prior art discloses all the limitations of a claim except a property or function and the examiner cannot determine whether or not the reference possesses properties which anticipate or render obvious the claimed invention, the examiner can shift the burden of proof to applicant.
The obviousness does not require absolute predictability of success all that is required is a reasonable expectation of success. See In re Kubin, 561 F.3d at 1360. The Court has held that "the test of obviousness is not express suggestion of the claimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them." See In re Rosselet, 146 USPQ 183, 186 (CCPA 1965). "There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art." Motorola, Inc. v. Interdigital Tech. Corp., 43 USPQ2d 1481, 1489 (Fed. Cir.1997). An obviousness determination is not the result of a rigid formula disassociated from the consideration of the facts of a case. Indeed, the common sense of those skilled in the art demonstrates why some combinations would have been obvious where others would not. See KSR Int'l Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) ("The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.").
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Isis A D Ghali whose telephone number is (571) 272-0595. The examiner can normally be reached on Monday through Friday, 8:30 AM to 5:00 PM EST.
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/ISIS A GHALI/Primary Examiner, Art Unit 1611
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