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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/22/26 has been entered.
Receipt is acknowledged of Amendments, Remarks, and an IDS filed on 04/22/26. Claim 1 has been amended, claims 3 and 19 have been canceled and no new claims have been added. Accordingly, claims 1-2 and 4-12 remain pending and under examination on the merits.
Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
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 pre-AIA 35 U.S.C. 103(a) 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.
Applicant’s claims
Claim 1 is drawn to an intranasal powder formulation in unit dose form comprising: i.) dihydroergotamine (DHE) or a pharmaceutically acceptable salt thereof that is present in the unit dose in an amount of about 6 mg; and ii.) a microcrystalline cellulose component comprising at least 15% of the total weight of the unit dose.
Claims 8 and 9 recite the mean particle size diameter of microcrystalline of about 100 µm or 30 µm or less.
Claims 1-2 and 4-12 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Nagata et al (US 20100178331) in view of Cook et al (US 20080287451) as evidenced by Merkus et al (US 20060147388).
Nagata et al teach a preparation for transnasal application, which comprises at least a complex comprising: a fluidability-improving component comprising a first crystalline cellulose (A) having specified powder properties, tricalcium phosphate (B) having specified powder properties, and a second crystalline cellulose (C) having specified powder properties or a starch (D) having specified powder properties; and a physiologically active substance (See abstract).
Nagata et al disclose that powdery nasal preparations need to be delivered into a nasal cavity from a capsule or blister pack by air flow generated by pressing the pump component of a nasal device. The invention “provide carriers and preparations with improved flowability, which deeply affects productivity in the process of automated capsule filling and issues related to a device's spray efficiency, by using a specific crystalline cellulose which is useful as a carrier of nasal administration” (See [0020] and [0023]).
The said physiologically active substance may be an analgesic including antimigraine agents such as sumatriptan, zolmitriptan, ergotamine; etc, (See [0049]).
Nagata et al teach the use of various types of Ceolus® and their derivatives (i.e. microcrystalline cellulose) in the said powder formulations as the crystalline cellulose (See [0074], [0077] and [0082]). Nagata et al also disclose that the average particle diameter of the first cellulose is preferably 10 to 25 µm, and more preferably 12 to 22 µm (See [0076]) or 30 µm or less (See [0091]), the average particle diameter of the second cellulose is preferably 150 µm or less, and is present from 5 to 30% (W/W) (See [0083]).
Nagata et al teach that the first crystalline cellulose may be present from 60 to 94.9 (W/W) % of the carrier composition and the second crystalline cellulose or starch may be present from 5.0 to 30 (W/W) % of the carrier composition (See claims 48-49).
Nagata et al lack a specific disclosure on the ergotamine being its derivative, dihydroergotamine mesylate or its amount. This is well known in the art as shown by Cook et al and as evidenced by Merkus et al.
Cook et al teach pharmaceutical compositions containing dihydroergotamine (DHE) and methods in which DHE is administered to patients for treatment of migraine without side effects or adverse effects (See Abstract).
It is disclosed that the said method involves administration of a unit dose comprising about 5.0 mg DHE or salts, hydrates, polymorphs, etc, (See [0050]). Any salt of DHE may be used but the mesylate salt is preferred (See [0066]).
Cook et al disclose an inhaler device comprising one or more unit doses of a DHE formulation wherein each unit dose is administered at a rate such that the peak plasma concentration (Cmax) is less than 10,000 pg/ml concentration in the circulating plasma in humans, and the time (Tmax) following administration when the peak plasma concentration is attained, is less than 30 minutes, or less than 20 minutes and most preferably 15 minutes after administration (See [0016]-[0017], [0029] and [0046]).
The said DHE formulation may be administered by buccal, intranasal or oral inhalation (See [0026], [0051], [0053] and claims 38 and 41).
In a preferred mode, the method of administration is by pulmonary inhalation using dry powder inhalers (See [0027], [0078], claims 39 and 42).
As evidenced by Merkus et al;
Merkus et al teach formulations suitable for nasal delivery of pharmacologically and therapeutically active agents for systemic activity, in particular for nasal powders containing drugs such as apomorphine and dihydroergotamine and their salts (See [0001]). The said powder usually has a range of particle sizes distributed around a mean particle size, which is in the range of from 5 to 150 µm (See [0007]). A suitable salt of dihydroergotamine is mesylate and/or tartrate (See [0033] and [0090]).
Merkus et al disclose a formulation comprising from 2.5 to 50% by wt of dihydroergotamine mesylate and 50-97% of an excipient (See claim 7). The said powdered pharmaceutical formulation suitable for nasal delivery containing: 0.5-50% by wt of active material and 50-99.5% by wt of excipient(s) (See [0014]). The said one or more excipient may be mannitol or microcrystalline cellulose (see claims 1 and 17).
The said formulation can be administered using a nasal insufflator or a passive device. For example, the formulation is placed in a capsule which is set in an inhalation or insufflation device. The required amount for a nasal administration of the said nasal formulation is between 1 and 50 mg, typically 1 to 20 mg, for example administered as about 5 to 20 mg per nostril (See [0047] and [0102]).
Merkus et al disclose the use of the said formulation in the manufacture of a medicament for use in therapeutic treatment of a human or animal body by nasal administration, wherein the medicament is for use in treatment of migraine (See [0049]).
It would have been obvious to a person of ordinary skilled in the art at the time the invention was made given the powdery formulation of Nagata et al comprising an ergotamine as the active agent sprayed via a nasal spray device, to have looked in the art for specific and related derivatives of the said active agent and its doses for effective treatment of subjects in need thereof. Cook et al teach a powdery formulation comprising DHE for nasal administration, wherein the formulation may comprise about 5 mg of DHE and wherein the Tmax is less than 30 minutes.
Furthermore, as evidenced by Merkus et al, nasal formulations comprising dihydroergotamine mesylate for quick relief of migraine headaches are disclosed and well known. As such one of ordinary skill in the art would have been more than motivated to have selected the mesylate salt of dihydroergotamine at its disclosed amounts for an effective and fast treatment of migraines because the art discloses it and its advantages. Nagata et al also disclose the effect of different size ranges of microcrystalline celluloses for achieving a better serum bioavailability of the formulation.
In other words, all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
Additionally, the claims would have been obvious because the technique for improving a particular formulation was part of the ordinary capabilities of a person of ordinary skill in the art, in view of the teaching of the technique for improvement in other situations.
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.
Claims 1-2 and 4-12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12,594,273. An obviousness-type double patenting rejection is appropriate because while the conflicting claims are not identical, the examined claims are not patentably distinct from the reference claims because the examined claims would have been obvious over the reference claims.
Specifically, the examined claims are drawn to an intranasal powder formulation in unit dose form comprising: i.) dihydroergotamine (DHE) or a pharmaceutically acceptable salt thereof in an amount of about 6 mg; and ii.) a microcrystalline cellulose component comprising at least 15% of the total weight of the intranasal powder formulation.
Reference claims are drawn to a nasal delivery device, comprising a pharmaceutical nasal dosage form comprising dihydroergotamine mesylate and microcrystalline cellulose; wherein dihydroergotamine mesylate is present in the pharmaceutical nasal dosage form in an amount of 6 mg to about 8 mg, wherein said microcrystalline cellulose is present in the pharmaceutical nasal dosage form in an amount from about 40% to about 60% w/w; and wherein said pharmaceutical nasal delivery device provides a Tmax of dihydroergotamine mesylate of less than or equal to about 30 minutes; and the nasal delivery device requires no priming.
The difference between the examined claims and the reference claims is that the examined claims are drawn to the formulation comprising about 6 mg of DHE and microcrystalline cellulose while the reference claims are drawn to a nasal delivery device comprising a formulation comprising about 6 mg of DHE and microcrystalline cellulose. The examined claims encompass all that is recited in the reference claims and thus would have been obvious over the reference claims.
The differences are minor and obvious.
Claims 1-2 and 4-12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 14-15, 17-20 of U.S. Patent No. 10,792,253. An obviousness-type double patenting rejection is appropriate because while the conflicting claims are not identical, the examined claims are not patentably distinct from the reference claims because the examined claims would have been obvious over the reference claims.
Specifically, the examined claims are drawn to an intranasal powder formulation in unit dose form comprising: i.) dihydroergotamine (DHE) or a pharmaceutically acceptable salt thereof in an amount of about 6 mg; and ii.) a microcrystalline cellulose component comprising at least 15% of the total weight of the intranasal powder formulation.
Reference claim 14 is drawn to an intranasal powder formulation comprising (of claim 1), wherein the intranasal pharmaceutical powder composition comprises: 1) about 1 to about 8 mg of the dihydroergotamine or a pharmaceutically acceptable salt thereof; 2) about 5 to about 15 mg of the mannitol; and 3) about 5 to about 15 mg of the microcrystalline cellulose.
The difference between the examined claims and the reference claims is that the examined claims are drawn to the formulation comprising about 6 mg of DHE and microcrystalline cellulose while the reference claims are drawn to a powdery nasal composition comprising about 1 to about 8 mg of DHE, mannitol and microcrystalline cellulose. The examined claims encompass all that is recited in the reference claims, as mannitol is not excluded. Thus, the examined claims would have been obvious over the reference claims.
The differences are minor and obvious.
Claims 1-2 and 4-12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 13-20 and 25 of U.S. Patent No. 12,263,162. An obviousness-type double patenting rejection is appropriate because while the conflicting claims are not identical, the examined claims are not patentably distinct from the reference claims because the examined claims would have been obvious over the reference.
Specifically, the examined claims are drawn to an intranasal powder formulation in unit dose form comprising: i.) dihydroergotamine (DHE) or a pharmaceutically acceptable salt thereof in an amount of about 6 mg; and ii.) a microcrystalline cellulose component comprising at least 15% of the total weight of the intranasal powder formulation.
Reference claim 1 is drawn to a method of treating or preventing a headache, comprising administering to a human subject a powdery pharmaceutical formulation that comprises 5 mg to about 7 mg of dihydroergotamine mesylate and about 18 to about 19 mg of microcrystalline cellulose.
The difference between the examined claims and the reference claims is that the examined claims are drawn to the formulation comprising about 6 mg of DHE and microcrystalline cellulose while the reference claims are drawn to a method of treating a subject in need of treatment comprising administering the said formulation via intranasal administration. The reference method requires and has incorporated the examined claims’s composition. Also, the examined claims encompass all that is recited in the reference claims, as mannitol is not excluded. Thus, the examined claims would have been obvious over the reference claims.
The differences are minor and obvious.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Kiechel et al (5,169,849),
Kiechel et al teach a nasal pharmaceutical composition incorporates a non-toxic agent which is capable of increasing the ciliary function e.g. caffeine and at least partially antagonizing the ciliary function depressant effect of the active agent e.g. dihydroergotamine or any other constituent present in the composition (See abstract).
Kiechel et al disclose that the said nasal formulations may be in a liquid or powder form (See col. 2, lines 60-63 and col. 5, lines 13-15). The active agent may be administered in free base form or in pharmaceutically acceptable acid addition salt form, e.g. the mesylate. Such salts in general have the same order of activity as the active agent. For example, dihydroergotamine may be administered in the form of the mesylate (See col. 3, lines 45-50). The said nasal pharmaceutical compositions are especially suitable for administration of active agents for the treatment of conditions which require quick relief, e.g. particularly and especially migraine (See col. 3, lines 54-58). The preferred amount of dihydroergotamine to be administered nasally is in the order of from about 0.5 to 5 mg (See col. 4, lines 3-6).
Kiechel et al further disclose a particularly preferred nasal pharmaceutical composition which contains an aqueous solution of 0.4% dihydroergotamine mesylate, 5% glucose and 1% caffeine (See col. 6, lines 54-40).
Henwood et al (US 20130178465),
Henwood et al teach intranasal formulations the unit dose is administered by a single nasal spray. The said unit dose is administered by a single nasal spray using a single dose spray device requiring no priming. The single dose can be administered through a single actuation of a nasal spray device. An examples of spray device that does not require priming includes, Aptar Unitdose Intranasal Systems (see [0067]).
Henwood et al teach that the said method further comprises administering one or more additional therapeutic agents, including an analgesic, such as a triptan and other compounds for migraine headaches (See [0069]).
The said the intranasal composition may be provided as a powder to be administered into the nasal cavity (See [0079]).
Response to Arguments
Applicant's arguments filed 04/22/26 have been fully considered but they are not persuasive.
The rejections of record have been modified. Applicant’s arguments so far as they pertain to the maintained references and rejections are discussed below.
Regarding the rejection of claims over Nagata, Merkus and Cook references, Applicant argues that none of the references teach or disclose the claimed amount of about 6 mg of DHE.
Specifically, Applicant argues that “To the contrary, Cook expressly teaches administration of relatively low doses of DHE to avoid adverse effects associated with high plasma concentrations, and specifically discloses unit doses less than 3 mg, with 1 mg identified as preferred. Cook, ¶¶ [0024], [0050], [0084]. A person of ordinary skill in the art, seeking to follow Cook's teachings, would have been motivated to reduce, not increase, the DHE dose in order to minimize side effects associated with peak plasma levels. The cited references do not provide, any teaching, suggestion, or motivation that would have led a person of ordinary skill in the art to modify the formulations of Cook to arrive at a unit dose of about 6 mg of DHE, nor any reasonable expectation that such a modification would be successful.” (See Remarks, page 9).
This is not found persuasive. Firstly, it is noted that the above rejection has been modified. Secondly, examined claims are drawn to a formulation in a unit dose comprising about 6 mg of DHE. The combination of Nagata et al and Cook et al, as evidenced by Merkus et al would have led one of ordinary skill in the art to the same compositions. One of ordinary skill in the art is more than capable of determining the amount of the components such as the active agents in a composition based on desire or need for the formulation. That is, “[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.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969); Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed.Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). See MPEP 2144.05.
Thirdly, regarding the argument that “Cook expressly teaches administration of relatively low doses of DHE to avoid adverse effects associated with high plasma concentrations, and specifically discloses unit doses less than 3 mg, with 1 mg identified as preferred. Cook, ¶¶ [0024], [0050], [0084].”, Cook et al teach that:
In one aspect of the invention, the method involves administration of an unit dose comprising about 0.5, 1.0, 2.0, 3.0 or 5.0 mg DHE or salts, hydrates, polymorphs prodrugs, ion pairs and metabolites thereof. (See [0050]), and,
In general, patients receive a total dosage of between 0.1 and 10.0 mg, preferably 0.5 to 5.0 mg, or more preferably 1.0-2.0 mg per migraine attack. The dose of the DHE formulation administered to an individual (such as human) will vary with the particular composition and the method of administration, such as to achieve the necessary biogenic amine receptor binding profile required for treating migraine without triggering side effects or adverse effects. (See [0066]).
Therefore, Cook et al, which compares the side effects and plasma concentrations of the powder nasal administration to IV administration, discloses that the dosage of DHE can be up to 10 mg, and preferably 5.0 mg per attack.
Thus, one of ordinary skill in the art given the powder compositions of Nagata et al and Cook et al would have been more than capable of determining the optimum range from the disclosed range with a reasonable expectation of success. In other words, this is what researchers do, optimization of result-effective variables through routine experimentation (MPEP 2144.05 IIA and B). There would have been a reasonable expectation of success due to the high level of skill in the art and the teachings of the references in the absence of evidence to the contrary, such as unexpected results. Cook et al also teach a solid formulation that can be intranasally administered to a subject and achieve a Tmax of less than 30 minutes.
Thus, the burden is on the Applicant to show that it’s claimed range would result in a different product that is materially distinguishable and unobvious.
The argument is also not convincing because a reference is relied upon for ALL that it teaches not the examples. That is, “It is well-established that consideration of a reference is not limited to the preferred embodiments or working examples, but extends to the entire disclosure for what it fairly teaches, when viewed in light of the submitted knowledge in the art, to a person of ordinary skill in the art. In re Boe, 355, F.2d 961, 148 USPQ 510, 510 (CCPA 1966).
Claims 1-2 and 4-12 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mina Haghighatian whose telephone number is (571)272-0615. The examiner can normally be reached M-F, 7-5 EST.
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/Mina Haghighatian/
Mina Haghighatian
Primary Examiner
Art Unit 1616
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