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
Claim 1-20 are pending and are under consideration in the instant office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted 10/25/2024 and 03/15/2023 complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits. See attached copy of the PTO-1449.
Priority
This is a continuation patent application claiming the benefit of priority under 35 U.S.C. § 120 to U.S. patent application No. 17/732,667, filed April 29, 2022, which is a continuation of U.S. patent application No. 16/899,353, filed June 11, 2020, now pending, which is a continuation-in-part of U.S. patent application No. 16/250,450, filed January 17, 2019, now abandoned, which is a continuation-in-part of U.S. patent application No. 15/995,875, filed June 1, 2018, now issued as U.S. Pat. No. 10,391,102, which is a continuation-in-part of U.S. patent application No. 15/903,529, filed February 23, 2018, now issued as U.S. Pat. No. 10,166,240, which is a continuation-in-part of US patent application No. 15/184,768, filed June 16, 2016, now issued as U.S. Pat. No. 9,918,993, which in turn claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. provisional patent application No. 62/182,130, filed June 19, 2015, the entire content of each of which is incorporated herein by reference. U.S. patent application No. 15/995,875, filed June 1, 2018, is also a continuation-in-part claiming the benefit of priority under 35 U.S.C. § 120 to U.S. patent application No. 15/903,615, filed February 23, 2018, now issued as U.S. Pat. No. 10,179,136, which is a continuation-in-part of 15/184,768, filed June 16, 2016, now issued as U.S. Pat. No. 9,918,993, which claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. provisional patent application No. 62/182,130, filed June 19, 2015.
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, 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-20 are rejected under 35 U.S.C. 103(a) as being unpatentable over by Louon et al. (British Journal of Ophthalmology, 1993,77:529-530) and Roelofse et al. (Anesth Prog. 51, 2004 pages 114-121) in view of Rudnic (Chapter 92, Oral solid dosage forms, Remington, 1995, pages 1615-1649) , Eppler et al. (US 2009/0061024) and Merkus et al. (US 7,700,588) (All references are cited in instant IDS dated 06/30/2022 except Merkus et al )
Instant claims are drawn to a method for inducing conscious sedation comprising orally administering to a patient in need thereof a pharmaceutical composition formulated for buccal and/or sublingual administration comprising a therapeutically effective dose of midazolam and a therapeutically effective dose of ketamine, wherein the therapeutically effective dose of midazolam comprises about 3 mg of midazolam and wherein the therapeutically effective dose of ketamine comprises about 50 mg of ketamine.
Louon et al. disclose intranasal administration of 025 ml/kg mixture containing 1.8 ml of midazolam (5 mg/ml) and 1.6 ml of Ketamine (50 mg/ml). Total dose of 0.9 mg Midazolam and 8 mg Ketamine for sedation for a baby receiving cryotherapy treatment for retinopathy of prematurity ( Page 529, left col., 2nd paragraph and Case report on page 529). Louon et al. disclose that pharmacokinetics of intranasal midazolam at a dose as low as 0 2 mg/kg showed that the hypnotic threshold of 100 ng/ml was obtained with 5-10 minutes and this correlated well with sedation. Pharmacokinetics of intranasal ketamine the dose was 4-6 mg/kg and the onset of action within 8-12 minutes. They also disclose that compared with intramuscular or intravenous routes, intranasal administration is a noninvasive, pain-free method and has fast onset of action. High bioavailability, rapid peak serum levels, and perhaps absorption through the cribriform plate result in a rapid onset of sedation (page 530, right col., 2nd paragraph). Louon et al. discloses sedation achieved in infants with this combination administered intranasally during an ophthalmic surgery such as retinopathy(entire document).
Roelosfe et al. discloses study evaluating the efficacy and safety of intranasal ketamine and midazolam for sedation and analgesic in pediatric patients undergoing dental surgery (Abstract). Roelosfe et al. discloses that Midazolam is a benzodiazepine that is widely used as a sedative in conscious sedation or monitored anesthetic care and that rapid uptake and high bioavailability of intranasal midazolam has been demonstrated in healthy volunteers and intranasal midazolam provide rapid, safe, and effective sedation in small children before anesthesia. They also disclose that Ketamine is a phencyclidine anesthetic agent that provides analgesic activity at subanesthetic doses. And it is an N-methyl-D-aspartate receptor antagonist with opioid-receptor activity. Roelosfe et al. disclose that Controlled studies and case reports on ketamine demonstrate efficacy in neuropathic and nociceptive pain and that premedication with intranasal administration of S+ ketamine (1-2 mg/kg) and midazolam (0.2 mg/kg) provides good conditions for induction of anesthesia in preschool children with adverse effects within an acceptable range (page 115, right col., 2nd paragraph). Roelosfe et al.. further discloses that the intranasal route is one of the most permeable and highly vascularized sites for drug administration, ensuring rapid absorption into the systemic circulation and onset of therapeutic action and it has been potentially explored as an alternative route for drugs with poor bioavailability and for the delivery of bio sensitive and high molecular-weight compounds such as proteins, peptides, steroids, and vaccines. They disclose that Direct systemic absorption bypasses the portal circulation (hepatic first pass effect) and may increase the bioavailability of nasally absorbed drugs. Added absorption enhancers, such as cyclodextrins, phospholipids, bio adhesive powder systems, and chitosan, improve nasal delivery (page 116, left col., under discussion). Their study demonstrated the safety and efficacy of using Midazolam and Ketamine combination which were the ease of administration, combined with rapid onset of action, good sedated and a smooth mask induction of anesthesia was experienced in the majority of children and finally an effective postoperative analgesia for multiple dental extractions was provided (page 120, left col.,2nd paragraph).
Louon et al. or Roelosfe et al. fails to specifically disclose the binder included in their composition of midazolam and ketamine used in their methods and fail to disclose Buccal or sublingual administration.
However, Formulating compositions for various routes of administration using different excipients including binders is well known in the art.
Rudnic discloses various oral dosage forms and the excipients included in the formulations. He teaches use of Binders in oral dosage form formulations, and that they impart cohesive qualities which ensures the tablet remains intact after compression and exemplifies polyethylene glycol as one of the binder examples (page 1617, left col., under binders). He further teaches Polyvinylpyrrolidone as a binder and teaches that most binders used in solution are polymeric in form (page 1618, 7th paragraph). He teaches other excipients typically used in solid dosage formulations such as flavoring agents which include artificial sweetening agents such as Aspartame (page 1620, under flavoring agents). Rudnic teaches troches which are also known as lozenges or pastilles are discoid-shaped solids containing the medicinal agent in a suitably flavored base which is either a hard sugar candy, glycerinated gelatin or the combination of sugar with mucilage to give it form. The Troches comprise drugs which include anesthetic and analgesic (page 1648, under Troches).
Eppler et al. discloses compositions comprising Ketamine which are effective in reducing the amount of anesthetic required to maintain anesthesia (abstract). Eppler et al. discloses that their compositions may be formulated for oral, parenteral, intramucosal, intranasal or rectal administration [0137].They teach compositions comprising ketamine and at least one pharmaceutically acceptable carrier [0145] and one or more other additives such as flavoring agents, lubricants, suspending agents, fillers, glidents or binders etc. [0148].
Merkus et al. discloses midazolam compositions formulated as a liquid, semi-liquid or semi-solid formulation for sublingual, buccal, rectal or any other transmucosal administration in the form of oromucoosal capsule , lollipop or any other form for transmucosal drug delivery( col.11, Lines 20-29)
With regards to instant claims 8-10 and the binders listed include derivatives of polyethylene glycol which is taught in the prior art as a suitable binder in tablet formulations and as such it would have been obvious to a skilled artisan to utilize any one of these agents such as polypropylene glycol or PEG-laureates etc. as binder in their formulation of tablet or troche.
As such it would have been prima facia obvious to a person of ordinary skill in the art to arrive at the instant claims motivated and guided by the combined teachings of the references’ above. Formulating compositions of ketamine and midozolam for different modes of administration including buccal/sublingual administration using appropriate excipients is very well known in pharmaceutical arts. An ordinarily skilled artisan would be motivated to formulate the combination of midazolam and ketamine into a convenient administrable formulation motivated by the prior art that this combination is suitable for to produce conscious sedation, procedural sedation or analgesia during invasive or non-invasive medical procedure which includes ophthalmic surgeries or dental procedure as taught by Louon et al. or Roelosfe et al. Accordingly, use of different excipients in various different formulations such as oral, buccal, Sublingual, parenteral, intranasal or rectal for the specific properties they impart on the composition is well know in the art as Eppler et al., Merkus et al. and Rudnic et al . As such a person of ordinary skill in the art is provided with ample suggestions and motivations to develop a method for inducing conscious sedation comprising orally administering to a patient in need thereof a pharmaceutical composition formulated for buccal and/or sublingual administration comprising a therapeutically effective dose of midazolam and a therapeutically effective dose of ketamine. Use of different excipients in the formulations and depending on the desired product it would have been prima facia obvious to a person of ordinary skill in the art to select appropriate agents at appropriate concentration and formulate the composition. The differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains because it would have been prima facie obvious to the skilled artisan to try different types of excipients to achieve the desired properties in the composition. Selection of excipients and the amounts to be used can be readily determined by one of ordinary skilled in the arts based upon experience and consideration of standard procedures and reference work in the field. It is noted that "[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). As such ordinarily skilled artisan will be imbued with at least a reasonable expectation of success in developing a method of providing sedation and analgesia in a patient during ophthalmic or dental surgical procedure with a formulated compositions of midazolam and ketamine as instantly claimed, especially in the absence of evidence to the contrary.
With regards to instant claims 16-19, Since both these agents are individually and together known to be useful in the method of providing sedation during surgery, it would have been obvious to a person of skill in the art to utilize it during any type of surgery which requires conscious sedation such as oral, dermatological or ophthalmic surgery.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
An obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but an examined application claim not is patentably distinct from the reference claim(s) because the examined claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985).
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9-12 of U.S. Patent: 9,918,993,(‘993) and claims 1-23 of US 10,179,136 (‘136) and claims 1-16 of US 12,083,126 (‘126)
Instant claims are drawn to a solid pharmaceutical composition formulated for buccal and/or sublingual administration comprising a benzodiazepine and an NMDA antagonist (Claim 1), comprising midazolam and ketamine (Claim 10) and comprising about 3 mg of midazolam and about 50 mg of ketamine (Claim 19) Instant claims are drawn to a method for inducing conscious sedation comprising orally administering to a patient in need thereof a pharmaceutical composition formulated for buccal and/or sublingual administration comprising a therapeutically effective dose of midazolam and a therapeutically effective dose of ketamine, wherein the therapeutically effective dose of midazolam comprises about 3 mg of midazolam and wherein the therapeutically effective dose of ketamine comprises about 50 mg of ketamine.
Claims of ‘993 are drawn to a pharmaceutical composition, comprising:
(a) a therapeutically effective quantity of a first pharmaceutically active compound selected from the group consisting of midazolam, diazepam, lorazepam, flunitrazepam, alprazolam, chlordiazepoxide, clonazepam and clorazepate, and pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof;
(b) a therapeutically effective quantity of a second pharmaceutically active compound selected from the group consisting of ketamine, dextrorphan, etomidate, methadone, memantine, amantadine, dextromethorphan, and pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof;
(c) a pharmaceutically suitable binder therefor; and
(d) optionally, a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is formulated as a solid item adapted for sublingual or buccal administration, the solid item being selected from the group consisting of a troche, a lozenge, a capsule, a pill, a cap and a bolus
Claims 1-23 of ‘136 are drawn to a pharmaceutical composition, comprising:
(a) a therapeutically effective quantity of a first pharmaceutically active compound selected from the group consisting of midazolam, diazepam, lorazepam, flunitrazepam, alprazolam, chlordiazepoxide, clonazepam and clorazepate, and pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof, in combination with a non-benzodiazepine compound selected from the group consisting of eszopiclone, ramelteon, zolpidem, and zaleplon;
(b) a therapeutically effective quantity of a second pharmaceutically active compound selected from the group consisting of ketamine, dextrorphan, etomidate, methadone, memantine, amantadine, dextromethorphan, and pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof;
(c) a pharmaceutically suitable binder therefor; and
(d) optionally, a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is formulated as a solid item adapted for sublingual or buccal administration, the solid item being selected from the group consisting of a troche, a lozenge, a capsule, a pill, a cap and a bolus
Claims 1-16 of ‘126 are drawn to a solid pharmaceutical composition formulated for buccal and/or sublingual administration comprising a therapeutically effective dose of midazolam and a therapeutically effective dose of ketamine.
Although the conflicting claims in the instant application and in the claims of ‘993 and ‘136 are not identical as stated above solid pharmaceutical, they are not patentably distinct from each other because ketamine and midazolam are already well known as userful as sedating agents and the utility instantly claimed will be inherent to the composition of ‘993, 136 and ‘126. As such the instant claims are obvious over the claims of ‘993, ‘136 and ‘126.
Claims 1-20 are rejected under the judicially created doctrine of obviousness-type double patenting over claims 1-19 of US patent 10,166,240 (‘240) , claims 1-19 of US patent 10,391,102 (‘102), claims 1-21 of US patent 10,555,952 (‘952)
Instant claims are as recited above.
Claims of ‘240 are drawn to A method for carrying out an invasive or a non-invasive medical procedure, comprising orally administering to a patient in need of conscious sedation, procedural sedation, analgesia, pre-sedation or a non-general anesthesia a pharmaceutical composition as the first step of the procedure, the pharmaceutical composition comprising: (a) a therapeutically effective quantity of a first pharmaceutically active compound selected from the group consisting of midazolam, diazepam, lorazepam, flunitrazepam, alprazolam, chlordiazepoxide, clonazepam and clorazepate, and pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof; (b) a therapeutically effective quantity of a second pharmaceutically active compound selected from the group consisting of ketamine, dextrorphan, etomidate, methadone, memantine, amantadine, dextromethorphan, and pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof; (c) a pharmaceutically suitable binder therefor; and (d) optionally, a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is formulated as a solid item adapted for sublingual or buccal administration, the solid item being selected from the group consisting of a troche, a lozenge, a capsule, a pill, a cap, and a bolus, to carry out the medical procedure thereby.
Claims of ‘102 are drawn to a method for inducing conscious sedation, procedural sedation, analgesia, pre-sedation or a non-general anesthesia in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising: (a) a therapeutically effective quantity of a first pharmaceutically active compound selected from the group consisting of midazolam, diazepam, lorazepam, flunitrazepam, alprazolam, chlordiazepoxide, clonazepam and clorazepate, and pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof; (b) a therapeutically effective quantity of a second pharmaceutically active compound selected from the group consisting of ketamine, dextrorphan, etomidate, methadone, memantine, amantadine, dextromethorphan, and pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof; (c) a pharmaceutically suitable binder therefor; and (d) optionally, a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is administered by a method selected from the group consisting of rectal administration, oral spray administration, transdermal administration, and transmucosal administration, to induce conscious sedation, procedural sedation, analgesia, pre-sedation or non-general anesthesia thereby.
Claims of ‘952 are drawn to A method for treating or mitigating sedative-induced nystagmus in a patient in need of conscious sedation, procedural sedation, analgesia, pre-sedation or a non-general anesthesia prior to undergoing a medical procedure comprising administering to the patient an effective amount of a pharmaceutical composition, the pharmaceutical composition comprising: (a) a therapeutically effective quantity of a first pharmaceutically active compound selected from the group consisting of midazolam, diazepam, lorazepam, flunitrazepam, alprazolam, chlordiazepoxide, clonazepam and clorazepate, and pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof; (b) a therapeutically effective quantity of a second pharmaceutically active compound selected from the group consisting of ketamine, dextrorphan, etomidate, methadone, memantine, amantadine, dextromethorphan, and pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof; (c) optionally, a pharmaceutically suitable binder therefor; and (d) optionally, a pharmaceutically acceptable excipient, thereby preventing or mitigating the occurrence of sedative-induced nystagmus resulting from administering the second pharmaceutically active compound alone to the patient for conscious sedation, procedural sedation, analgesia, pre-sedation or a non-general anesthesia.
Although the conflicting claims in the instant application and in the ‘240 and ‘102 are not identical as stated above, they are not patentably distinct from each other because instant claims of ‘240 , ‘102 and ‘952 all recite a method of inducing sedation with the instantly claimed composition of midazolam and ketamine and also recites the buccal or sublingual pharmaceutical composition comprising these two drugs. Therefore, subject matter disclosed claims 1-25 of the instant application is fully taught in claim 1-19 of patent ‘240 and ‘102 and claims 1-21 of ‘952 , hence anticipates the instant claims.
Conclusion
Claims 1-20 are rejected. No claims are allowed
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/SAVITHA M RAO/Primary Examiner, Art Unit 1691
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