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 .
The request to participate in the PPH pilot program and petition to make special has been granted on 12/20/23. Accordingly, the Application is examined under Special status.
Receipt is acknowledged of Remarks, and an IDS filed on 10/01/25. No claims have been amended, canceled or added. Accordingly, claims 1-12 and 19 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Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn.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 from about 5 mg to about 6 mg; and ii.) a microcrystalline cellulose component comprising at least 15% of the total weight of the intranasal powder formulation.
Claims 8 and 9 recite the mean particle size diameter of microcrystalline of about 100 µm or 30 µm or less.
Claim 19 is directed to a Tmax value of the formulation after nasal delivery.
NOTE: The said Tmax is related to the outcome of the formulation after delivery, which 1- does not affect the scope of the claimed composition and 2- would be expected to be the same form the formulations of the prior art.
Claims 1-12 and 19 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Nagata et al (US 20100178331) in view of Merkus et al (US20060147388) and Oki et al (WO 2004073729, or US 7,638,138).
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 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 Merkus et al. Oki et al also teach particle size of the MCC and Tmax of the said powders.
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]).
It is disclosed that the required amount for a nasal administration of a nasal formulation may be, for example, between 1 and 50 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]).
Oki et al ‘138 teach compositions for nasal administration, which comprise a pharmaceutical, and as the carrier thereof, crystalline cellulose with a specific particle diameter and/or partially pregelatinized starch. Such compositions improve the in vivo absorption efficiency of pharmaceuticals (See abstract). Starch with a mean particle diameter of 20 to 100 µm is used (See col. 4, lines 18-20).
The particle size distribution of crystalline cellulose includes about 85 wt % or more of the crystalline cellulose particles having a particle diameter distribution within the entire range of 20 to 60 µm. Specifically, commercially available Avicel® PH-F20 or PH-M15 can be used after size classification or as it is.
The nasal formulations of Oki et al also comprise one or more physiologically active agents (See col. 2, line 63 to col. 3, line 28).
Oki et al further tabulate the results of administration of the said nasal powder and discloses that the formulations achieved a Tmax of less than 30 minutes (See Tables 1 and 9).
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, it’s doses for effective treatment of subjects in need thereof and device specifics for better delivery. Merkus et al disclose nasal formulations comprising dihydroergotamine mesylate for quick relief of migraine headaches. As such one of ordinary skill in the art would have been more than motivated to have selected the mesylate salt of ergotamine 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.
It further 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 and Merkus et al comprising dihydroergotamine mesylate and a microcrystalline cellulose delivered from a nasal device to have incorporated Oki et al’s teaching on the particle size diameter of microcrystalline cellulose with a reasonable expectation of success. Merkus et al do not specifically recite the mean particle size of the microcrystalline cellulose, but they disclose the particle size of the powder which includes microcrystalline cellulose. The powder is said to have a particle size in the range of from 5 to 150 µm. Nagata et al also provides guidance on the effective particle size range for the cellulose base and and Oki et al teach that the cellulose has a particle size of diameter of 20 to 100 µm and preferably in the range of 20-60 µm. Accordingly, one of ordinary skill in the art having possession of Oki et al’s teachings would have been further motivated to make sure the particle size range of the cellulose is less than 100 µm and preferably 30 µm or less. Additionally, Oki et al disclose powder formulations for intranasal delivery comprising an active agent and a cellulose excipient wherein the powders achieve a Tmax of less than 30 minutes.
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.
Claims 1-12 and 19 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Nagata et al (US 20100178331) in view of Merkus et al (US 20060147388) and Cook et al (US 20080287451).
The teachings of Nagata et al and Merkus et al are delineated above and incorporated herein. The references do not expressly disclose a Tmax for the disclosed formulations. This is taught by Cook et al. Cook et al also discloses the concentration range of DHE.
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, oral inhalation, etc, (See [0026], [0051], [0053] and claims 38 and 41).
In a preferred mode, the method of administration is by pulmonary inhalation using aerosols, dry powder inhalers, pressurized metered dose inhalers (pMDIs) and the like (See [0027], [0078], claims 39 and 42).
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, its doses for effective treatment of subjects in need thereof and device specifics for better delivery. Merkus et al disclose nasal formulations comprising dihydroergotamine mesylate for quick relief of migraine headaches. As such one of ordinary skill in the art would have been more than motivated to have selected the mesylate salt of ergotamine 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.
Nagata et al teach a nasal device/spray for use in the delivery of the said formulation. There is no recitation that the said device requires priming. Additionally, Henwood et al also disclose a nasal formulation delivered to the subject’s nasal cavity via a device that does not require priming.
Additionally, Nagata et al and Merkus et al teach i8ntransal administration of a formulation comprising about 6 mg of DHE mesylate. Cook et al also teach that the said formulation is expected to achieve a Tmax of less than 30 minutes, preferably less than 20 minutes.
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 1-12 and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 13-14, 16-17, 25 and 44-45 of U.S. Patent No. 9,101,539 in view of Merkus et al (US20060147388) and/or Cook et al (US 20080287451).
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 in view of Merkus et al and/or Cook et al.
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 from about 5 mg to 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 composition comprising a therapeutic agent, wherein at least some of the therapeutic agent is present in a freebase form, and the therapeutic agent consists of two particle size distribution ranges, the first being less than 20 microns and the second being from about 38 microns to about 100 microns. The active agent may be an ergotamine, such as dihydroergotamine and the excipient may be microcrystalline cellulose. Merkus et al teach powder formulations for nasal administration comprising dihydroergotamine mesylate for a quick relief of migraine headaches. Merkus et al disclose the amount of DHE per nostril and the amount of CMC in mg and percentage. It would have been obvious to extrapolate the examined claims from the reference claims because while examined claims are drawn to a nasal dosage form comprising DHE, the reference claims are drawn to the same composition but do not recite DHE as one of the active agents. Merkus et al discloses powder formulations for nasal administration comprising DHE and as such renders obvious the specific active agent of dihydroergotamine mesylate in nasal formulations. It would have been obvious to have incorporated the specific active agents and the amount of it as taught by Merkus et al in the formulations of the reference claims to arrive at the instant claims. Additionally, Cook et al teach powder compositions for intranasal administration comprising about 5 mg of DHE and excipients.
It would have been obvious to extrapolate the examined claims from the reference claims because while examined claims and the reference claims are drawn to an intranasal formulation comprising a dosage of DHE and microcrystalline cellulose. The modifications are minor and obvious.
Claims 1-12 and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 7,638,138 in view of Merkus et al (US20060147388) and/or Cook et al (US 20080287451).
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 in view of Merkus et al and/or Cook et al.
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 from about 5 mg to 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 granular composition comprising a powdered pharmaceutical agent, a carrier substance which is crystalline cellulose powder and has a particle size distribution of 10 wt % or fewer particles with a diameter smaller than 25 µm; 20 to 60 wt % particles with a diameter of 25 to 38 µm; 20 to 60 wt % particles with a diameter greater than 38 µm and smaller than or equal to 53 µm; and the remaining particles having a diameter greater than 53 µm. The active agent is selected from various peptides. Merkus et al teach powder formulations for nasal administration comprising dihydroergotamine mesylate for a quick relief of migraine headaches. It would have been obvious to extrapolate the examined claims from the reference claims because while examined claims are drawn to a nasal dosage form comprising DHE, the reference claims are drawn to the same composition but do not recite DHE as one of the active agents. Merkus et al discloses powder formulations for nasal administration comprising DHE and as such renders obvious the specific active agent of dihydroergotamine mesylate in nasal formulations. Merkus et al disclose the amount of DHE per nostril and the amount of CMC in mg and percentage. It would have been obvious to have incorporated the specific active agents and its amount of Merkus et al in the formulations of the reference claims to arrive at the instant claims.
Additionally, Cook et al teach powder compositions for intranasal administration comprising about 5 mg of DHE and excipients.
Claims 1-12 and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 8,435,554 in view of Merkus et al (US20060147388) and/or Cook et al (US 20080287451).
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 in view of Merkus et al and Cook et al.
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 from about 5 mg to 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 powdered composition comprising an active peptide (drug) and a carrier consisting of crystalline cellulose having a mean sieving particle diameter of less than 50 µm. Merkuset al teach powder formulations for nasal administration comprising dihydroergotamine mesylate for a quick relief of migraine headaches. It would have been obvious to extrapolate the examined claims from the reference claims because while examined claims are drawn to a nasal dosage form comprising DHE, the reference claims are drawn to the same composition but do not recite DHE as one of the active agents. Merkus et al discloses powder formulations for nasal administration comprising DHE and as such renders obvious the specific active agent of dihydroergotamine mesylate in nasal formulations. Merkus et al disclose the amount of DHE per nostril and the amount of CMC in mg and percentage. It would have been obvious to have incorporated the specific active agents of Merkuset al in the formulations of the reference claims to arrive at the instant claims.
Additionally, Cook et al teach powder compositions for intranasal administration comprising about 5 mg of DHE and excipients.
Claims 1-12 and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 6,906,027 in view of Merkus et al (US20060147388) and/or Cook et al (US 20080287451).
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 in view of Merkus et al and/or Cook et al.
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 from about 5 mg to 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 granulated composition for nasal administration comprising powdered insulin and a carrier consisting of crystalline cellulose having a mean sieving particle diameter of from 10-350 µm. Merkuset al teach powder formulations for nasal administration comprising dihydroergotamine mesylate for a quick relief of migraine headaches. It would have been obvious to extrapolate the examined claims from the reference claims because while examined claims are drawn to a nasal dosage form comprising DHE, the reference claims are drawn to the same composition but do not recite DHE as one of the active agents. Merkus et al discloses powder formulations for nasal administration comprising DHE and as such renders obvious the specific active agent of dihydroergotamine mesylate in nasal formulations. Merkus et al disclose the amount of DHE per nostril and the amount of CMC in mg and percentage. It would have been obvious to have incorporated the specific active agents of Merkuset al in the formulations of the reference claims to arrive at the instant claims.
Additionally, Cook et al teach powder compositions for intranasal administration comprising about 5 mg of DHE and excipients.
It also would have been obvious to one of ordinary skill in the art to have made different selection of particle size ranges for the crystalline cellulose carrier particles because the reference claims broadly disclose average particle sizes that lie in the range of 10-350 micron. In other word, “Where 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, 105 USPQ 233 (CCPA 1955).
Claims 1-12 and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 8,673,360 in view of Merkus et al (US 20060147388) and/or Cook et al (US 20080287451).
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 in view of Merkus et al and/or Cook et al.
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 from about 5 mg to 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 powdery composition for intranasal administration comprising a non-peptide drug wherein the drug is an opioid receptor agonist or 5-HT1 receptor agonist and a carrier consisting essentially of crystalline cellulose. Merkus et al teach powder formulations for nasal administration for quick relief of migraine headaches comprising dihydroergotamine mesylate or apomorphine and an excipient including crystalline cellulose. Merkus et al also provide guidance on the amount of DHE in the said powdery composition.
Additionally, Cook et al teach powder compositions for intranasal administration comprising about 5 mg of DHE and excipients.
The differences are that the examined claims comprise DHE while reference claims comprise opioid receptor agonist or 5-HT1 receptor agonist. It would have been obvious to one of ordinary skill in the art to have substituted the non-peptide drug with DHE because as Merkus et al teach there is evidence that DHE is suitable for nasal administration and very effective in treating migraine when nasally administered.
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 10/01/25 have been fully considered but they are not persuasive.
First argument is that the Action incorrectly referred to DHE as a salt of ergotamine and that based on this factual error, there is no rational to support a conclusion of obviousness (See Remarks, pages 4-5).
Applicant is correct in that DHE is not a salt of ergotamine rather a synthetic derivative. Accordingly, the Action has been corrected. However, this error is not sufficient to remove the rejections. DHE is as ergotamine related compound and is used for the same purpose and in the same dosage form. That is Nagata teach powder formulations comprising a cellulose and an ergotamine for nasal administration to treat migraines. Merkus teach powder compositions comprising DHE and a cellulose for nasal administration for treating migraines. As such, the rejection has shown clearly that one of ordinary skill in the art is motivated to select a known derivative of ergotamine as taught by Merkus with a reasonable expectation of success.
Next argument is that DHE and ergotamine are different active agents with different structures and different pharmacologic profile. Applicant argues that DHE must be administered at higher doses than ergotamine and there are significant clinical differences between the two. Given these differences, o POSA would not reasonably expect to predictably modify the teachings of Nagata substituting ergotamine with DHE (See Remarks, page 5).
The above argument is not found convincing. The Action did not suggest a plug-and-play substation of DHE for ergotamine as Applicant argues. Nagata teach powder formulations comprising a cellulose and an ergotamine for nasal administration to treat migraines. Merkus teach powder compositions comprising DHE and a cellulose for nasal administration for treating migraines. The prior art that suggests a powder formulation comprising DHE also provides for its dosage amounts. Thus, the dosing regimen has been provided for DHE. One of ordinary skill in the art is not left to determine the dosing amount of DHE from a teaching of ergotamine.
Then Applicant argues that Merkus does not provide any reason to believe that DHE can be substituted for ergotamine, much less the dose (See remarks, pages 5-6).
This argument is also not found persuasive because Nagata teach a powder formulation for nasal administration comprising an active including ergotamine and microcrystalline cellulose. Merkus teach a powder formulation comprising microcrystalline cellulose and an active agent including DHE and provide guidance on the dosage amount. Thus, the two references together would have led one of ordinary skill in the art to have prepared a powder formulation comprising DHE and a microcrystalline cellulose for nasal administration with a reasonable expectation of an effective treatment.
Applicant’s arguments regarding Suzuki reference are persuasive and as such this reference and the rejection relying on it have been withdrawn.
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 5 to about 6 mg of DHE. Applicant believes that the Office’s assertion that Merkus provides this teaching is inaccurate.
Specifically, Applicant argues that “The Office attempts to equate claim 1’s requirement of an absolute amount of about 5 to about 6 mg of DHE with the percentage-based teachings of claims 4 and 5, and then cites Merkus’s disclosure of formulations containing about 2.5—50% active agent. See Office Action, p. 23 (stating that “[t]he claims state that an amount of about 5 mg to about 6 mg of DHE is equivalent to about 0.4 to about 23% of DHE in the said powder formulation (See claims 4-5).”). Claim 1 recites a specific, absolute amount of DHE, whereas claims 4 and 5 recite relative percentages of DHE within a formulation. These limitations are not interchangeable, nor does the broad disclosure of percentages in Merkus equate to or disclose the precise claimed amount. In fact, Merkus’s disclosure of an expansive 2.5—50% range is so broad that it cannot reasonably be said to teach, suggest, or render obvious the narrow and specific dosage range of about 5 to about 6 mg required by claim 1” (See Remarks, page 8).
This is not found persuasive. Firstly, Applicant’s attempt to distinguish between claims 1 and 4-5 by referring to the “about 5 mg to about 6 mg” DHE as an absolute amount and the range of “about 0.4 to about 23%” in claim 4 or “about 0.3 to about 18%” in claim 5 as relative is unpersuasive. Both are ranges of amounts, one in mg and one in percentages and both use the term about to increase the range. Secondly, claims 4 and 5 depend on claim 1, which means they incorporate the limitations of claim 1. Thus, in claim 4, the powder composition comprises a unit dose comprising from about 5 to about 6 mg of DHE, which is within the amount of about 0.4 to about 24% of the formulation. While the two ranges are interchangeable, they are very much linked and have to support each other.
Therefore, Merkus clearly teaching that the active agent, i.e. DHE or apomorphine can be in the powder at about 2.5 to 50% meets the claimed amount of from about 0.4 to about 24%. Merkus et al claim - A formulation according to claim 1, containing 2.5-50% by wt dihydroergotamine mesylate and/or tartrate and/or other water soluble pharmaceutically acceptable salts in crystalline state, 50-97.5% by wt of excipient(s)-. Thus, Merkus et al meets the same concentration range as in claims 4-5, which depend on claim 1.
Additionally, Merkus teach that the required amount for a nasal administration of a nasal formulation according to the invention may be, for example, between 1 and 50 mg, typically 1 to 20 mg, for example administered as about 5 to 20 mg per nostril. Thus, Merkus teaches up to 50% of the formulation can be DHE and that each unit dose can comprise about 5 mg of DHE.
Regarding Merkus’s range of 2.5 to 50% being an expansive range, the argument is also not persuasive because it provides guidance to one of ordinary to select the desired amount from the disclosed range. Also, the claimed range of 0.4% to 24% is a broad range as well. Furthermore, it is noted that Applicant states that 5-6 mg range of claim 1 is not interchangeable with the percentage range of claims 4-5, but then compares 5-6 mg to 0.4 to 24% (See Remarks, page 8, last three lines).
Regarding the dose and/or the amount ranges, it is held 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); 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.
Thus, one of ordinary skill in the art given the powder compositions of Nagata and Merkus are 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.
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.
Applicant’s arguments against Cook reference is that Cook teaches the exact opposite of Merkus with regard to particle size and their deposition site. Applicant argues that Merkus teaches against small particles which can deposit in the lung while Cook teaches particles for lung delivery (See Remarks, page 9).
This argument is similarly underperceive. In this regard, the courts have held that "[i]t is impermissible within the framework of section 103 to pick and choose from any one reference only so much of it as will support a given position, to the exclusion of the other parts necessary to the full appreciation of what such reference fairly suggests to one of ordinary skill in the art." In re Wesslau, 353 F.2d 238, 241 (C.C.P.A. 1965); see also Bausch & Lomb, Inc. v. Barnes-Hind/Hydrocurve, Inc., 796 F.2d 443,448-49 (Fed. Cir. 1986).
Applicant is comparing Merkus’s disclosure of a powder for nasal administration to Cook’s pulmonary application. However, as the rejection clearly states, Cook teaches formulations comprising DHE for pulmonary inhalation or nasal administration. Clearly, for pulmonary inhalation the particle size should be that of inhalable range for deposition in the lung, whereas for nasal administration, the particle size is larger and the goal is nasal deposition. Cook specifically discloses formulations that would achieve optimum pharmacokinetic profile including Cmax and Tmax. Cook states:
According to the invention, DHE is administered by any method at a rate such that the Cmax is less than 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000 pg/ml concentration in the circulating plasma in humans, and the time following administration when the peak plasma concentration is attained (Tmax) occurs within 10, 15, 20, 30, 45 or 60 minutes after administration. (See at least [0046]).
The invention also relates to suitable solid, liquid or aerosol formulations of DHE that, when administered to a mammal under appropriate conditions, achieve the desired delivery profile defined by AUC, Cmax and Tmax values listed above (See [0052).
According to the methods of the invention a DHE formulation may be administered by any mode necessary to achieve the desired delivery profile defined by Cmax and Tmax values listed above, including but not limited to, by intravenous, intra-arterial, intraperitoneal, intrapulmonary, oral, sublingual, buccal, intranasal, oral inhalation, intravesicular, intramuscular, intra-tracheal, subcutaneous, iontophoretic, transdermal administration. (See [0053]).
Therefore, Cook teaches a solid formulation that can be intranasally administered to a subject and achieve a Tmax of less than 30 minutes.
This 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).
With regard to the rejection of claims under obviousness type double patenting over the reference patents, Applicant’s argument is that the reference claims do not recite the claimed amount of DHE and Merkus et al does not remedy this deficiency (See Remarks, Pages 11-12).
The above arguments are not found persuasive as the guidance on the amounts of DHE and CMC are provided by either the references or Merkus et al and/or Cook et al as stated above.
Claims 1-12 and 19 are rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Mina Haghighatian/
Mina Haghighatian
Primary Examiner
Art Unit 1616