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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 9/26/2025 has been entered.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-53, in the reply filed on 8/17/2023 is acknowledged.
Applicant’s election without traverse of:
(i-a) terpenoid;
(ii-a) generalized seizures;
(iii-a) food effect dose adjusting to compensate, claim 27;
(iv-b) 2.5 to 30 mg, claim 29;
(v) polyvinyl pyrrolidone as part of a mucoadhesive matrix;
(vi) a pharmaceutical film with a residence time of less than 30 minutes in an oral cavity, claim 43; and
(vii) at least about 5% of the diazepam is absorbed via a gastrointestinal route, claim 5;
in the reply filed on 8/17/2023 is acknowledged.
Claim 59 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/17/2023.
Claims 4, 6-8, 11-25, 28, 30-40, 42, 44-46 and 48-58 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/17/2023.
Response to Arguments
Applicants' arguments, filed 9/26/2025, 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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. They constitute the complete set presently being applied to the instant application.
Claim Objections
Claim 1 is objected to because of the following informalities: the language of lines 5-6 is duplicative: “within 1 hour” is duplicative of “1 hour or less”, and should refer to the recited time period in one manner or the other. Appropriate correction is required.
Information Disclosure Statement
The listing of references in the specification (p. 102) is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The incorporation of essential material in the specification by reference to an unpublished U.S. application, foreign application or patent, or to a publication is improper. Applicant is required to amend the disclosure to include the material incorporated by reference, if the material is relied upon to overcome any objection, rejection, or other requirement imposed by the Office. The amendment must be accompanied by a statement executed by the applicant, or a practitioner representing the applicant, stating that the material being inserted is the material previously incorporated by reference and that the amendment contains no new matter. 37 CFR 1.57(g).
The attempt to incorporate subject matter into this application by reference to the 19 references listed on p. 102 of the specification is ineffective because it is improper to incorporate by reference to material in each of these publications.
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) 1, 5, 9-10, 26-27, 29, 41, 43, 47 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rogawski et al. (“Diazepam buccal film for the treatment of acute seizures”; 2019 5 Nov; Epilepsy & Behavior; 101(2019):106537, pp. 1-4; IDS reference) as applied to claims 1-2, 5, 9-10, 26-27, 29, 41, 43 above, and further in view of Schobel et al. (US 2017/0290776 A1; 2017; IDS references).
Claim 1 has been amended to require “reaching a therapeutic window within 1 hour or less”.
Rogawski teaches Diazepam buccal film (DBF; i.e., the same dosage form as that described in the instant specification) is a compact, easily administered diazepam formulation. When placed onto the buccal mucosa inside the cheek, DBF adheres firmly and then rapidly dissolves, delivering diazepam transbucally and via the gastric route (a bimodal delivery profile, a type of multimodal delivery profile, instant claim 1) (abstract). A buccal soluble film formulation of diazepam (DBF; LibervantTM, Aquestive Therapeutics) is under development that has several favorable characteristics and overcomes many of the disadvantages of other nonparenteral dosage forms used for acute seizure treatments (reading on claim 9) (Fig. 1). The thin film, which is less than the size of a postage stamp, is affixed to the buccal mucosa inside the cheek. Placement can be either by the patient or by a caregiver. Diazepam is absorbed transbucally and is also swallowed (bimodal delivery, amended claim 1), so that a portion of the dose is transported to the stomach and adsorbed by the small intestine. The polymer hydroxypropyl methylcellulose is used to hold diazepam and excipients in a uniform distribution throughout the film (the polymer HPMC is construed as a matrix, which releases diazepam, reading on claim 1, line 3). The film has a mucoadhesive surface so that it adheres to the buccal mucosa (reading on claim 41). It begins to dissolve immediately on application to the mucosa releasing diazepam (construed as satisfying the less than 30 minutes residence time in the oral cavity of claim 43).
Figure 2 shows about 420 ng/ml Tmax is achieved for a 15 mg dose for healthy adult males under fasting conditions. Regarding food delay, Cmax obtained with DBF was 204 ng/mL for 17.5 mg dose under fed conditions (Section 7). The difference between 420 and 204, or 216, corresponds to an amount in excess of 50%, which is attributed to a reduction due to the swallowed portion interacting with food. This is taken as evidentiary at least 50% (clearly in excess of 5%) of the 15 mg dosage form is absorbed via a gastrointestinal route, reading on the elected embodiment of claim 5.
The fed dose of section 7 uses a maximum dose of 17.5 mg; this is in excess of the 15 mg dose, used in Figure 2, and in excess of the 12.5 mg dose in adults with epilepsy, including tonic-clonic seizures (construed as Applicant elected generalized seizures, claims 9-10). Cmax was 180-190 ng/ml for the seizure patients, compared to 204 ng/mL for fed patients receiving 17.5 ng/mL. Thus, the elected embodiment of adjusting a dose of diazepam to compensate for a food effect by increasing the dose to offset the food effect such that a subject achieves a safe and efficacious dose (claims 26-27) is present in the teachings of Rogawski.
All doses discussed fall within the elected range of claim 29. Claim 1 has been amended to require delivering diazepam and a permeation enhancer from a matrix to a subject, the same subject matter previously recited in claim 3 (now canceled).
While the examiner construes the polymer taught to be a matrix (claim 1), this is a reasonable construction, but not explicitly taught. The Examiner notes that tonic-clonic seizures taught are reasonably construed to be generalized (relevant to claim 10, but this is not explicit. Rogawski teaches a mucoadhesive, but PVP elected, is not explicitly taught (this component is not recited in claim 41). The teaching of immediate start of dissolution is reasonably construed to read on the elected less than 30-minute residence time of claim 43, but this time period is not explicit.
Rogawski does not mention a permeation enhancer delivered from the matrix, now required by the amendment to claim 1. Rogawski does not teach the elected terpenoid permeation enhancer, recited in claim 47.
Schobel teaches pharmaceutical compositions having enhanced active component permeation properties (abstract). Figure 15 demonstrates amount of Diazepam permeated in the presence of a series of permeation enhancer; increased flux rates are also depicted for diazepam in Figure 16.
In general a pharmaceutic composition can include a polymeric matrix, a pharmaceutically active component in the polymeric matrix, and an adrenergic receptor interacter. In certain embodiments, the pharmaceutical composition can further include a permeation enhancer. An adrenergic receptor interacter can be an adrenergic receptor blocker. [0004]. In certain embodiments the adrenergic receptor interacter can be Applicant elected terpenoid [0005]; claim 3. In certain embodiments, the pharmaceutical composition can be a film further comprising a polymeric matrix, the pharmaceutically active component being contained in the polymeric matrix [0006]; claim 6.
In certain embodiments the pharmaceutically active component can be diazepam [0020]; claim 19. Example 2 tests diazepam applied to the buccal (cheek) surface, testing various permeation enhancers.
In certain embodiments, the polymeric matrix can include Applicant elected polyvinylpyrrolidone [0029]-[0030]; claims 24-25.
Benzodiazepines are some of the most effective drugs in the treatment of acute seizures; the benzodiazepines most commonly used to treat status epilepticus include diazepam (Valium). The pharmaceutically active components in a pharmaceutical composition (e.g., pharmaceutical composition film) can be a treatment for, inter alia, Epilepsy with generalized tonic-clonic seizures [0110].
It can be preferable to use films that are moderate dissolving films. Which can dissolve rather quickly, but also have a good level of mucoadhesion. The dissolution rate is most desirably between about 1 minute and about 20 minutes, while providing an acceptable mucoadhesion level such that the film is not easily removable once it is placed in the oral cavity of the user [0104].
It would have been obvious to select components taught Schobel, in the method of treating seizures with polymer matrix type films of Schobel, including diazepam from the matrix and Applicant elected terpenoid, taught by Schobel as adrenergic receptor, giving Applicant elected permeation enhancer required by claim 47 and reading on amended claim 1. Based on Rogawski, bimodal delivery profile would be the result of bioadhesion of the film to the buccal surface, giving claim 1 (bimodal delivery profile was previously found to be anticipated, but, Rogawski does not teach the permeation enhancer being delivered from a matrix). Inclusion of a permeation enhancer is characteristically achieved by following the terpenoid, clearly preferably by Schobel, per claim 3 in the matrix. Additionally, an additional permeation enhancer would also have been obvious, based on claim 2 of Schobel. The purpose of adding a permeation enhancer would have been to enhance the portion of diazepam delivered via the buccal surface. Extension of seizures to Applicant elected generalized (tonic-clonic) type seizures, in view of the suitability of diazepam for treating these generalized seizures taught by Schobel. It would have been obvious to include PVP in the matrix, based on the suitability of this polymer matrix material taught and claimed by Schobel. Regarding the film dissolution time of elected claim 43, moderate dissolving films are preferred by Schobel, having balance of less than 30 minutes dissolution and sufficient bioadhesion to the buccal tissue, to optimize the buccal adsorption.
Thus, because the above noted limitations reasonably construed as being present in Rogawski are explicitly taught by Schobel, their inclusion would have been obvious, based on applying the explicit teachings of Schobel as being obvious. Schobel provides consideration of materials and characteristics that lead to suitable films of diazepam; their incorporation into the Rogawski films would have been obvious based on these components being used for the same type films of diazepam, and the clearly preferred buccal administration route.
Regarding the elected terpenoid, this component is taught and claimed by Schobel, rendering the inclusion prima facie obvious. The instant claimed permeation enhancer characteristic would have been present, absent evidence to the contrary.
It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph).
Regarding the amended language of claim 1, reaching a therapeutic window within 1 hour or less, this language describes a characteristic of the recited steps of the method. Rogawaski clearly teaches doses of 5, 10 and 15 mg, that achieves Cmax by 60 min (10 or 15 mg doses) or by 45 min (lowest dose). The Cmax level, ranging from about 170-420 (Figure 2), is construed to reach a therapeutic window within 1 hour.
Regarding Applicant elected food, this can delay absorption of oral diazepam and reduce the Cmax level; the median Tmax was 1 hour (reaching a therapeutic window within 1 hour (p. 3, section 7).
Applicant argues that Rogawski does not teach a permeation enhancer. For reasons set forth in the rejection, it would have been obvious to select components taught Schobel, in the method of treating seizures with polymer matrix type films of Schobel, including diazepam from the matrix and Applicant elected terpenoid, taught by Schobel as adrenergic receptor, giving Applicant elected permeation enhancer required by claim 47 and reading on amended claim 1. Based on Rogawski, bimodal delivery profile would be the result of bioadhesion of the film to the buccal surface, giving claim 1 (bimodal delivery profile). Inclusion of a permeation enhancer is characteristically achieved by following the terpenoid, clearly preferably by Schobel, per claim 3 in the matrix. Additionally, an additional permeation enhancer would also have been obvious, based on claim 2 of Schobel. The purpose of adding a permeation enhancer would have been to enhance the portion of diazepam delivered via the buccal surface. Extension of seizures to Applicant elected generalized (tonic-clonic) type seizures, in view of the suitability of diazepam for treating these generalized seizures taught by Schobel. It would have been obvious to include PVP in the matrix, based on the suitability of this polymer matrix material taught and claimed by Schobel. Regarding the film dissolution time of elected claim 43, moderate dissolving films are preferred by Schobel, having balance of less than 30 minutes dissolution and sufficient bioadhesion to the buccal tissue, to optimize the buccal adsorption.
Thus, adoption of permeation enhancers taught by Schobel would have been obvious. And inclusion of both terpenoid (claim 3), as a species of adrenergic receptor interacter (claim 1), in combination with a permeation enhancer (claim 2) is claimed, and thus obvious to include in obvious buccal film that delivers a bimodal delivery profile. Release from the matrix taught would have been obvious to formulate. At least some of the permeation enhancers of Schobel are clearly depicted to increase amounts of diazepam permeated (Figure 15). Inclusion of the permeation enhancers is clearly obvious, motivated to increase the amount of drug delivered via the buccal (a mucosal) tissue. While a series of permeation enhancers are explicitly taught, inclusion of terpenoids is clearly taught, and the rejection documents that this elected compound would also have functioned as permeation provider.
Examiner disagrees with arguments about In re Best and In re Fitzgerald not being applicable because the method is a process, not products. The point about terpenoid functioning as permeation enhancer is clearly known, even according to Applicant’s election. The cited case law is clearly relevant.
Applicant argues that without a permeation enhancer bimodal delivery does not occur. This position is incorrect. The rejection clearly documents bimodal delivery from teachings of Rogawski. And the rejection further documents obviousness of inclusion of a permeation enhancer based on benefits of increasing diazepam.
Regarding the bimodal delivery, this is clearly taught by Rogawski: Rogawski teaches Diazepam buccal film (DBF; i.e., the same dosage form as that described in the instant specification) is a compact, easily administered diazepam formulation. When placed onto the buccal mucosa inside the cheek, DBF adheres firmly and then rapidly dissolves, delivering diazepam (1) transbucally and (2) via the gastric route (this is clearly a bimodal delivery profile, a type of multimodal delivery profile, instant claim 1) (abstract). Thus, Applicant is in error with the argument that the bimodal delivery is allegedly not taught in the prior art. This is a teaching of bimodal delivery of the diazepam.
Examiner notes that the obviousness rejection relies on articulated reasoning with a rational underpinning supporting the legal conclusion of obviousness.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ali Soroush can be reached at (571)272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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TIMOTHY P. THOMAS
Primary Examiner
Art Unit 1614
/TIMOTHY P THOMAS/Primary Examiner, Art Unit 1614