DTEAILED 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 .
Priority
The instant application is a 371 National Stage Entry of PCT/US21/40084 filed on July 1, 2021 which claims benefit to domestic application No. 63/046,743 filed on July 1, 2020.
Status of Claims
Acknowledgement is made of original (2), amended (1, 3-17) claims filed on August 14, 2023. Claims 1-17 are pending in instant application.
Information Disclosure Statement
The information disclosure statements filed on April 28, 2023, August 12, 2024 have been considered except where lined through.
Specification
i. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see one hyperlink at p. 15 ¶[0068], two at p. 27 ¶[0133], four at p. 41 References [3], [9], [11], two at p. 46 References [58], [65]). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
ii. The disclosure is objected to because of the following informalities:
The specification states “The same two dogs were each dosed at 2042 IV at 10 mg/kg. The results are provided in Tables 4 and 5.” (emphasis added, see instant spec. at p. 30 ¶[0148]—[0150]). However, Tables 4 and 5 recite dose levels of 30 mg/kg in the leftmost column of each table. Similarly, the specification states “Table 9: Summary of an individual Rat NPT-2042 Concentration-Time Data following an Oral Dose of 10 mg/kg NPT-2042” (emphasis added, see instant spec. at p. 32 ¶[0166]) and “Table 10: Summary of an individual Rat Bumetanide Concentration-Time Data following an Oral Dose of 10 mg/kg NPT-2042” (emphasis added, see instant spec. at p. 33 ¶[0167]) but Tables 9 and 10 recite dose levels of 30 mg/kg in the leftmost column of each table.
iii. The title of the invention not in accordance with MPEP since the word “novel” is recited, “NOVEL PHARMACEUTICAL COMPOSITIONS”. Furthermore, the title of the invention is not descriptive (i.e. “PHARMACEUTICAL COMPOSITIONS”). Furthermore, the title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
Per MPEP § 606, The words listed below are not considered as part of the title of an invention, these words should not be included at the beginning of the title of the invention and will be deleted when the Office enters the title into the Office’s computer records, and when any patent issues. The term "new" will not be deleted when it is a part of a proper name, such as "New York". Similarly, the term "design" will not be deleted when it is a part of a term, such as "Design-aiding apparatus...". A, An, The, Improved, Improvement(s) in/for/of, New, Novel, Related to, Design, Design for/of (a), Ornamental design, Ornamental Furthermore, the title of the invention is not descriptive.
The following title is suggested: COMPOSITIONS COMPRISING BUMETANIDE PRODRUGS FOR TREATING SEIZURE DISORDERS. A title should describe the product and/or method in detail.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a) – Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.— The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 3-5, 7-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The Written Description Guidelines for examination of patent applications indicates:
“the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice…or by disclosure of relevant, identifying characteristics, i.e., structure or other physical characteristics and/or other chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show applicant was in possession of the claimed genus.” (Federal Register, Vol. 66, No. 4, pp. 1099-1111, Friday January 5, 2001, see especially p. 1106 col. 3; see also MPEP § 2164).
In instant case, the claims are directed to a formulation comprising an active agent (bumetanide morpholinoamide, bumetanide diethylamide, and/or bumetanide dibenzylamide) and:
One or more excipient to increase bioavailability of the one or more active agent (instant claim 1 and dependent product claims 2, 6, 10, and dependent method claims 11-17)
One or more excipient wherein the minimum AUC is 57 ng*h/mL or less for immediate release formulated dose and a total AUC of 114 ng*h/mL or less over a 24 h period with sustained release formulated dose (see instant claim 3 and depend claims 4-5, 7-9)
wherein the minimum AUC is 45 ng*h/mL or less for immediate release formulated dose and a total AUC of 84 ng*h/mL or less over a 24 h period with sustained release formulated dose (see instant claim 4)
wherein the minimum AUC is 42 ng*h/mL or less for immediate release formulated dose and a total AUC of 84 ng*h/mL or less over a 24 h period with sustained release formulated dose (see instant claim 5)
wherein a minimum Cmax is 25 ng/mL (see instant claim 7)
wherein a minimum Cmax is 20 ng/mL (see instant claim 8)
wherein a minimum Cmax is 18 ng/mL (see instant claim 9)
wherein the composition provides an extended release profile of the active agent of 1 week, 2 weeks, 3 weeks, or 4 weeks (see instant claim 10)
The claims encompass a genus of formulations comprising bumetanide morpholinoamide, bumetanide diethylamide, and/or bumetanide dibenzylamide which are defined by functional characteristics (see above a-h). The phrase “a pharmaceutical composition comprising” is open-ended and does not exclude any other ingredients from being present together with the active agent, only that the formulation comprises an active agent and an excipient. The broadest reasonable interpretation of an excipient is a substance other than active pharmaceutical ingredients in finished pharmaceutical dosage forms (see Kerlin et. al.1 at p. 738 right col. “6.1 Excipients”). The claims are thus being reasonably interpreted as: a composition comprising bumetanide morpholinoamide, bumetanide diethylamide, and/or bumetanide dibenzylamide, and at least one other substance, limited by certain physiochemical properties which do not exclude the presence of other compounds. This genus is simply a wish to know the identity of such a composition that will satisfy the physiochemical properties.
Accordingly, there is insufficient written description encompassing the formulations of the claims wherein the formulation provides the claimed pharmacokinetic properties as disclosed in the claims because the relevant identifying characteristics of the genus (the absent additional structure(s) resulting in said pharmacokinetic properties) are not set forth in the specification as filed, commensurate in scope with the claimed invention. Per MPEP § 2163(I), to satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement." Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002) (see MPEP § 2163.03(V)). The instant specification does not clearly allow persons of ordinary skill in the art to recognize that Applicant invented what is claimed.
A description of a component in terms of its function rather than its structure fails to distinguish said component from any others with the same function. Applicant has not disclosed enough relevant, identifying characteristics, such as structure, sufficient to show possession of the claimed genus. Mere idea or function is insufficient for written description; a description of what a material does rather than what it is, usually does not suffice (see Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406, see also MPEP § 2163 (II)(A)(3)(a)).
In the instant case, Applicant exemplifies in vivo animal models comprising NPT-2042 via oral administration at a 30 mg/kg dosage, noting no other components (see instant spec. at p. 29 Example 4 Table 3, at p. 31-33 Example 5 Table 9), via IV administration at 10 mg/kg, noting no other components (see instant spec. at p. 30 Example 4 Table 4 and at p. 34 Example 5 Table 11), and bolus dosing at 10 mg/kg, noting no other components (see instant spec. at Example 4 Table 6 and at p. 35 Example 5 Table 13). Applicant lists “prophetic examples of formulations” (see instant spec. at pp. 27-29 Tables 1 and 2) describing administration routes and forms but no additional components and no discussion or showing of which excipients are necessary for certain pharmacokinetic functions.
In absence of structural characteristic that are shared by a genus of a composition comprising bumetanide morpholinoamide, bumetanide diethylamide, and/or bumetanide dibenzylamide and at least one other substance, wherein the formulation provides the claimed pharmacokinetic properties as disclosed in the instant claims, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus.
Suggested Amendment
The Examiner suggests amending the claims to include the specific components that achieve the currently claimed function.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 15 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 15 recites the phrases “…Symptomatic,…” (p. 4 line 15), “Other undetermined epilepsies not defined above” (line 21), and “Special syndromes” (p. 5 line 1).
Regarding “Symptomatic”, it is unclear what it is in reference to. “Symptomatic epilepsies” are already recited in the claim (p. 4 line 4).
Regarding “Other undetermined epilepsies not defined above”, it is unclear what is included or excluded from the phrasing. Is it yet-to-be-discovered types of epilepsy? Is it an epilepsy with yet-to-be-determined subcategories such as focal?
Regarding “Special syndromes”, a search of the prior art does not reveal a medically-accepted recognized term so it Is unclear what is excluded or included by the term.
Accordingly, the metes and bounds of claim 15 are not clear.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-15 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by US 2017/0246131 A12 to Partridge.
Regarding claims 1-9 an active agent, Partridge teaches bumetanide morpholinoamide (NPT-2024, see Partridge at p. 172 Example 125), bumetanide diethylamide (see Partridge claims 192-194 and at p. 159 Example 13), and bumetanide dibenzylamide (see Partridge claims 195-196 and at p.159 Example 15).
Regarding claims 1-9 and an excipient and formulations, Partridge discloses oral as and intravenous preparations, including formulating with microcrystalline cellulose, hydroxypropyl cellulose, or magnesium stearate (see Partridge at p. 176 ¶[0609]-[0610]) or propylene glycol, ethyl alcohol, water, buffers such as sodium benzoate and benzoic acid, or preservatives such as benzyl alcohol stearate (see Partridge at p. 176 ¶[0611]-[0612]). The instant specification discloses the above excipients: hydroxypropyl cellulose, microcrystalline cellulose, magnesium stearate (instant spec. at p. 14 ¶[0066] lines 15, 21, and 28), propylene glycol (instant spec. at p. 10 ¶[0054] line 2), water, ethanol (instant spec. at p. 10 ¶[0055] lines 4 and 5), benzoic acid and sodium benzoate (instant spec. at p. 13 ¶[0066] lines 4 and 5).
Further regarding claim 6 and formulations, Partridge discloses oral, sublingual, parenteral, implantation, nasal, and inhalational administration (see Partridge at pp. 146-147 ¶[0377]) including sublingual tablets (see Partridge at p. 147 ¶[0381]) or transdermal patches (see Partridge at p.147 ¶[0383]).
Regarding all claims and functional limitations, the prior art does not explicitly teach the disclosed composition excipients “increases bioavailability” or discloses any AUC or Cmax values. In addition to disclosing excipients as in instant application discussed above, Partridge teaches the dosage may be preferably formulated for: immediate release, extended release, pulse release, variable release, controlled release, timed release, sustained release, delayed release, long acting, and combinations thereof (see Partridge at pp.154-155 ¶[0429]), and may be monitored using standard pharmacological models known in the art (see Partridge at p. 155 ¶[0430]).
The office does not have the facilities and resources to provide the factual evidence needed in order to establish that the formulations of bumetanide N-morpholinoamide that will result from the teachings of the prior art do not possess the same material, structural and functional characteristics of the formulation claimed in the instant application. In the absence of evidence to the contrary, the burden is on the applicant to prove that the formulation used in the instantly claimed method is different from those taught by the prior art and to establish patentable differences (see MPEP § 2112.01).
Regarding claims 11-15 and a method of treating, Partridge teaches the bumetanide prodrugs disclosed are taught for treating seizures (see Partridge at p. 172, see also at p. 176 Table 6, at p. 178 Table 8, at p. 177 ¶[0617] IP Administration, at p. 179 ¶[0618]-[0619], at p. 180 ¶[0628], at p. 181 Table 11, at p. 182 ¶[0649]).
Accordingly, claims 1-15 are anticipated by Partridge.
Claims 1-10 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by U.S. Patent No. 8,008,283 B23 to Hochman.
Regarding claims 1-10 and active agents, Hochman teaches bumetanide diethylamide and bumetanide dibenzylamide (see Hochman at col. 39 Example 7 and at col. 40 Example 8).
Regarding claims 1-10 and excipients, Hochman teaches the pharmaceutical compositions may comprise excipients (see Hochman at col 32 ¶1) or biologically active or inactive compounds (see Hochman at col. 30 ¶3). Hochman also teaches the compounds may be administered with delivery systems that facilitate crossing the blood/brain barrier (see Hochman at col. 6 ¶3).
Further regarding claim 6 and formulations, Hochman teaches the compositions may be formulated for various administration routes including oral tablets, nasal aerosol sprays, and transdermal gels (see Hochman at col. 31 ¶2 – col. 33 ¶4).
Further regarding claims 3-5, 7-10 and functional limitations, the prior art does not explicitly teach the disclosed composition excipients “increases bioavailability” or discloses any AUC or Cmax values. However, Hochman discloses “[t]he compositions described herein may be administered as part of a sustained release formulation” (see Hochman at col. 32 ¶4). Hochman also discloses “[c]ompositions for injection will include the active ingredient together with suitable carriers including propylene glycol-alcohol-water, isotonic water, sterile water for injection (USP), emulPhor™-alcohol-water, cremophor-EL™or other suitable carriers known to those skilled in the art” (see Hochman at col. 31 ¶3). Instant specification states, “[b]y definition, when a medication is administered intravenously, its bioavailability is 100%” (see instant spec. at p. 4 ¶[0014]). Therefore Hochman’s injection embodiment with a disclosed carrier fulfills the limitation of an excipient to increase bioavailability of the active agent.
The office does not have the facilities and resources to provide the factual evidence needed in order to establish that the formulations of bumetanide N-morpholinoamide that will result from the teachings of the prior art do not possess the same material, structural and functional characteristics of the formulation claimed in the instant application. In the absence of evidence to the contrary, the burden is on the applicant to prove that the formulation used in the instantly claimed method is different from those taught by the prior art and to establish patentable differences (see MPEP § 2112.01).
Accordingly, claims 1-10 are anticipated by Hochman.
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 for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Partridge as applied to claims 1-15 above.
The prior are differs from the instant claims as follows: While Partridge teaches formulations comprising the bumetanide prodrugs, Partridge does not specify further administering additional therapeutic agents.
However,
Partridge uses “comprising” language which does not exclude additional components (see Partridge at claims 192-197). Partridge also discloses second agents for treatment may be used in combination with the disclosed compositions (see Partridge at pp.156-157 ¶[0444]-[0454], listing dozens of therapeutics including anti-convulsants such as gabapentin, pregabalin, carbamazepine, lamotrigine, topiramate, felbamate, tiagabine, diazepam rectal, phenobarbital, phenytoin, primidone, valproate, vigabatrin, oxcarbazepine, zonisamide, levetiracetam), and can be administered in the same formulation (see Partridge at p. 157 ¶[0446]).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Per MPEP § 2144.06(I), "[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). It would have been obvious to one skilled in the art to combine one seizure disorder treatment (a bumetanide prodrug) with another therapeutic agent (e.g. an anticonvulsant) for the same purpose of treating a seizure disorder as taught by the prior art.
Furthermore, it is well-within the ordinary skill in art to include additional components in a seizure treatment composition for the same purpose as taught by the prior art (treating seizures).
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Claims 11-17 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent No. 8,008,283 B24 to Hochman as applied to claims 1-10 above.
Regarding claims 16-17 and further administering therapeutic agents, Hochman teaches the compounds may be administered with other known treatment agents (see Hochman at col. 5 ¶6).
The prior art differs from the instant application as follows: While Hochman teaches compositions comprising the same instant active components, Hochman does not specify the utility of treating seizures.
Regarding claims 11-15 and a method of treating, Hochman teaches compounds for treating neuropathic pain (see Hochman at col 4 ¶1), which has the same underlying mechanism as seizures (see Hochman at col. 2 ¶1 – col. 4 ¶1).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Per MPEP § 2144.07, a prima facie case of obviousness exists for a known material based on its suitability for its intended use. In instant case, Hochman teaches instant active components for treating neuropathic pain, noting neuropathic pain and seizures have underlying mechanism causes involving NKCC. It would have been obvious to one skilled in the art that a neuropathic pain treatment could be used as a treatment for a seizure disorder because the active component modulates NKCC activity, which is involved in both neuropathic pain and seizures (as taught by Hochman).
Furthermore, it is well-within the ordinary skill in art use a known substance to treat a known disease. Furthermore it is well-within the ordinary skill in the art to identify relevant disease mechanisms when determining treatment strategies.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
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 conflicting claims 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) 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 www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
NSDP Rejection I
Claims 1-15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3-4 of U.S. Patent No. U.S. Patent No. 8,008,283 B25 to Hochman. Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant composition claims 1-10, US’283 claims compositions comprising bumetanide analogs including bumetanide diethylamide and bumetanide dibenzylamide with a carrier, excipient, or diluent (see US’283 claims 3-4).
Regarding instant method claims 11-17 and functional limitations, per MPEP §804(II)(B)(1), the court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Sun Pharm. Indus., Ltd. v. Eli Lilly & Co., 611 F.3d 1381, 95 USPQ2d 1797 (Fed. Cir. 2010). In particular, when ascertaining the scope of the reference’s claim(s) to a compound, the examiner should consider the reference’s specification, including all of the compound’s uses that are disclosed. See Sun Pharm. Indus., 611 F.3d at 1386-88, 95 USPQ2d at 1801-02. US’283 discloses the utility of treating neuropathic pain (see US’283 at col 4 ¶1), which has the same underlying mechanism as seizures (see US’283 at col. 2 ¶1 – col. 4 ¶1). While US’283 does not explicitly claim the composition excipients “increases bioavailability” or discloses any AUC or Cmax values, US’283 discloses “[t]he compositions described herein may be administered as part of a sustained release formulation” (see US’283 at col. 32 ¶4). US’283 also discloses “[c]ompositions for injection will include the active ingredient together with suitable carriers including propylene glycol-alcohol-water, isotonic water, sterile water for injection (USP), emulPhor™-alcohol-water, cremophor-EL™or other suitable carriers known to those skilled in the art” (see US’283 at col. 31 ¶3). Instant specification states, “[b]y definition, when a medication is administered intravenously, its bioavailability is 100%” (see instant spec. at p. 4 ¶[0014]). Therefore US’283’s claimed compositions, formulated for injection to treat a subject as disclosed, would fulfill the instantly claimed limitation of an excipient to increase bioavailability of the active agent.
The office does not have the facilities and resources to provide the factual evidence needed in order to establish that the formulations of bumetanide N-morpholinoamide that will result from the teachings of the prior art do not possess the same material, structural and functional characteristics of the formulation claimed in the instant application. In the absence of evidence to the contrary, the burden is on the applicant to prove that the formulation used in the instantly claimed method is different from those taught by the prior art and to establish patentable differences (see MPEP § 2112.01). Accordingly, the claims are drawn to overlapping compositions for treating disorders susceptible to NKCC modulation.
Provisional NSDP Rejection I
Claims 1-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22, 31-35 of copending Application No. 18/680,4636 (reference application) as evidenced by Maver et. al.7 Although the claims at issue are not identical, they are not patentably distinct from each other.
The applicable analysis for Nonstatutory Double Patenting is set forth in MPEP § 804(II), and specifically MPEP § 804(II)(B). MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis. The instant analysis is an obviousness analysis.
Regarding instant composition claims 1-10, App’463 claims a composition comprising up to 10 mg/kg of bumetanide dibenzylamide and carboxymethyl cellulose (App’463 claim 1) or a bumetanide amide prodrug in a capsule (App’463 claim 31).
Regarding instant method claims 11-17, App’463 claims an intended use of treating seizures (see App’463 at claims 1, 31).
The copending claims differ as follows: While App’463 claims a composition with an instant active component and an excipient, App’463 does not specify in the claims if the excipient increases the biovailability of the active agent, and additionally claims properties of the composition (App’463 claims 2-22, 32-35).
However,
Regarding the functional property of the excipient, carboxymethylcellulose is a well-known biocompatible polysaccharide tailorable for controlled drug release (see exemplary reference Maver at p. 2 left col. ¶5 – right col. ¶1 and at p. 6 Figure 3a-d, CMC = carboxymethylcellulose).
Regarding the functional properties additionally claimed in App’463, The additional properties are understood to be met by the structural limitations of the composition claimed (e.g. a composition of App’463 claim 1 comprising bumetanide dibenzylamide and carboxymethyl cellulose will have the further claimed properties of App’463 claims 2-22, and a composition of App’463 claim 31 will have the further claimed properties of App’463 claims 32-35). The composition of App’463 claim 1 is encompassed by instant application claim 1 (a composition comprising bumetanide dibenzylamide and an excipient) and thus the functions of the composition (App’463 claims 2-22, 32-35) are also encompassed. In addition, an instant application claim 1 composition is understood to be encompassed by App’463 claim 31 (a composition comprising a bumetanide amide prodrug).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Provisional NSDP Rejection II
Claims 1-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-21, 23-24, 32 of copending Application No. 18/238,0918 (reference application) as exemplified by Michaelsen et. al.9 Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant composition claims 1-10, App’091 claims compositions comprising bumetanide dibenzylamide (App’091 claims 16-18, 23-24, 32), or a bumetanide analog (App’091 claims 19-20) including bumetanide dibenzylamide, bumetanide diethylamide, or bumetanide morpholinoamide (App’091 claim 21) with specific ranges of defined excipients.
Regarding instant method claims 11-17, per MPEP §804(II)(B)(1), the court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Sun Pharm. Indus., Ltd. v. Eli Lilly & Co., 611 F.3d 1381, 95 USPQ2d 1797 (Fed. Cir. 2010). In particular, when ascertaining the scope of the reference’s claim(s) to a compound, the examiner should consider the reference’s specification, including all of the compound’s uses that are disclosed. See Sun Pharm. Indus., 611 F.3d at 1386-88, 95 USPQ2d at 1801-02. App’901 discloses the utility of treating seizure disorders (see App’091 at p. 1 ¶[0002]).
The copending claims differ as follows: While App’901 claims compositions with instant active agents, App’901 claims additional components in the compositions.
However,
Instant application compositions still encompass the compositions claimed by App’901 because the instant claims do not exclude additional components. The additional components claimed in App’901 (30-35% polyoxyl 35 castor oil aka the solubilizer Kolliphor® EL, 30-35% glyceryl monolinoleate aka the solubilizer Maisine® CC, 30-35% soybean oil, 0-0.16% antioxidant or preservative, 2-2.5% ethanol) are a formulation of well-known drug delivery system for increasing bioavailability referred to in the art as SNEDDS, self-nanoemulsifying drug delivery systems (see exemplary reference Michaelsen at p. 180 left col. and at p. 181 right col. ¶2, “The SNEDDS were composed of soybean oil (27.5% (w/w)), Maisine 35-1 (27.5% (w/w)), Kolliphor RH40 (35% (w/w)), and absolute ethanol (10% (w/w))”). The additional components claimed in App’901 thus fulfill the instantly claimed limitation of one or more excipients to increase bioavailability of the one or more active agents.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Provisional NSDP Rejection III
Claims 1-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 24-43 of copending Application No. 19/223,41110 (reference application) in view of Nan et. al11. Although the claims at issue are not identical, they are not patentably distinct from each other.
The applicable analysis for Nonstatutory Double Patenting is set forth in MPEP § 804(II), and specifically MPEP § 804(II)(B). MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis. The instant analysis is an obviousness analysis.
Regarding instant composition claims 1-10, App’411 claims compositions comprising bumetanide prodrugs or analogs (App’411 claims 24-43).
Regarding instant method claims 11-17, App’411 claims methods of treating seizures (App’411 claim 24).
The copending claims differ as follows: While App’411 claims compositions comprising bumetanide prodrugs or analogs, App’411 does not specify the instant active agents or excipients and claims additional properties.
However,
Regarding “bumetanide prodrug or analog”, the instant composition active agents (bumetanide morpholinoamide, bumetanide diethylamide, bumetanide dibenzylamide) are encompassed by the claimed limitation of a composition comprising a bumetanide prodrug or analog in App’411.
Regarding instant application and an excipient to improve bioavailability, Nan teaches formulating the anti-epileptic low water solubility drug carbamazepine (see Nan at p. 257 left col) utilizing a supersaturated self-microemulsifying drug delivery system (S-SMEDDS) to improve bioavailability (see Nan at p. 258 left col.).
Therefore, it would have been obvious to one of ordinary skill in the art to arrive at the instantly claimed invention with a reasonable expectation of success in view of the copending application for at least the following reason(s):
Per MPEP § 2143(I)(D), a prima facie case of obviousness exists for applying a known technique to a known method or product ready for improvement to yield predictable results. It would have been obvious to improve upon App’411’s anti-seizure composition by using a known S-SMEDDS technique because the prior art teaches S-SMEDDS improves bioavailability of an anti-seizure medication (as taught by Nan).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Provisional NSDP Rejection IV
Claims 1-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 110-129 of copending Application No. 18/922,26912 (reference application) as exemplified by Michaelsen. Although the claims at issue are not identical, they are not patentably distinct from each other.
The applicable analysis for Nonstatutory Double Patenting is set forth in MPEP § 804(II), and specifically MPEP § 804(II)(B). MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis. The instant analysis is an obviousness analysis.
Regarding instant composition claims 1-10, App’269 claims pharmaceutical compositions comprising bumetanide dibenzylamide (App’269 claims 110-124), or a bumetanide analog (App’269 claims 126-127, 129) including bumetanide dibenzylamide, bumetanide diethylamide, or bumetanide morpholinoamide (App’269 claim 128) and at least one solubilizer (App’269 claims 110-125, 129), or an oral lymphatic targeting excipient (App’269 claim 126-128).
Regarding instant method claims 11-17, App’269 claims treating a patient in need. Per MPEP §804(II)(B)(1), the court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Sun Pharm. Indus., Ltd. v. Eli Lilly & Co., 611 F.3d 1381, 95 USPQ2d 1797 (Fed. Cir. 2010). In particular, when ascertaining the scope of the reference’s claim(s) to a compound, the examiner should consider the reference’s specification, including all of the compound’s uses that are disclosed. See Sun Pharm. Indus., 611 F.3d at 1386-88, 95 USPQ2d at 1801-02. App’269 discloses the utility of treating a seizure disorder (see App’269 at p. 1 ¶[0002]).
The copending claims differ as follows: While App’269 claims pharmaceutical compositions comprising instant active agents, App’269 further claims additional composition components.
Instant application compositions still encompass the compositions claimed by App’269 (App’269 claims 110-124) (e.g. a composition comprising bumetanide dibenzylamide) because the instant claims do not exclude additional components. In addition, App’269 encompasses instant compositions (App’269 claims 126-127, 129) (e.g. a composition comprising a bumetanide analog). Furthermore, the additional components claimed in App’269 (e.g. polyoxyl 35 castor oil aka the solubilizer Kolliphor® EL, glyceryl monolinoleate aka the solubilizer Maisine® CC, soybean oil, ethanol) are a formulation of well-known drug delivery system for increasing bioavailability referred to in the art as SEDDS, self-emulsifying drug delivery systems (see exemplary reference Michaelsen at p. 180 left col. and at p. 181 right col. ¶2, “The SNEDDS were composed of soybean oil (27.5% (w/w)), Maisine 35-1 (27.5% (w/w)), Kolliphor RH40 (35% (w/w)), and absolute ethanol (10% (w/w))”). The additional components claimed in App’901 thus fulfill the instantly claimed limitation of one or more excipients to increase bioavailability of the one or more active agents. Moreover, it is within the skill of an artisan, and routine, to adjust the amount of a components in a composition to find an optimum composition (see MPEP § 2144.05).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Provisional NSDP Rejection V
Claims 1-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 71-72 of copending Application No. 18/367,90013 (reference application) in view of Nan. Although the claims at issue are not identical, they are not patentably distinct from each other.
The applicable analysis for Nonstatutory Double Patenting is set forth in MPEP § 804(II), and specifically MPEP § 804(II)(B). MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis. The instant analysis is an obviousness analysis.
Regarding instant composition claims 1-10, App’900 claims administering bumetanide analogs (App’900 claim 71) including bumetanide dibenzylamide or bumetanide diethylamide (App’900 claim 72).
Regarding instant method claims 11-17, App’900 claims methods of treating epilepsy or seizure disorder (see App’900 claim 71).
The copending claims differ as follows: While App’900 claims methods of treating seizure disorders with instant active agents, App’900 does not specify additional excipients.
However,
App’900 encompasses instant compositions because the claims do not exclude further administering an excipient.
Regarding instant application and an excipient to improve bioavailability, Nan teaches formulating the anti-epileptic low water solubility drug carbamazepine (see Nan at p. 257 left col) utilizing a supersaturated self-microemulsifying drug delivery system (S-SMEDDS) to improve bioavailability (see Nan at p. 258 left col.).
Therefore, it would have been obvious to one of ordinary skill in the art to arrive at the instantly claimed invention with a reasonable expectation of success in view of the copending application for at least the following reason(s):
Per MPEP § 2143(I)(D), a prima facie case of obviousness exists for applying a known technique to a known method or product ready for improvement to yield predictable results. It would have been obvious to improve upon App’900’s anti-seizure composition by using a known S-SMEDDS technique because the prior art teaches S-SMEDDS improves bioavailability of an anti-seizure medication (as taught by Nan).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
The specification is objected to.
Claims 1-17 are rejected.
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/S.R./Examiner, Art Unit 1627
/Kortney L. Klinkel/Supervisory Patent Examiner, Art Unit 1627
1 Roy L. Kerlin and Xiantang Li. "Chapter 24 - Pathology in Non-Clinical Drug Safety Assessment" In Haschek and Rousseaux's Handbook of Toxicologic Pathology (Third Edition; Wanda M. Haschek, Colin G. Rousseaux, Matthew A. Wallig, Eds.; Academic Press: 2013, pp. 725-750. DOI: 10.1016/B978-0-12-415759-0.00024-8
2 Cite No. 3 in the IDS filed 4/28/23. Hereinafter Partridge.
3 Published August 30, 2011. Hereinafter Hochman.
4 Published August 30, 2011. Hereinafter Hochman.
5 Published August 30, 2011. Hereinafter US’283.
6 CON of PCT/US2023/030238 filed August 15, 2023, has PRO 63/398,480 filed August 16, 2022. Hereinafter App’463.
7 Maver et. al. "Carboxymethyl cellulose/diclofenac bioactive coatings on AISI 316LVM for controlled drug delivery, and improved osteogenic potential" Carbohydrate Polymers, 2020, 230, 115612, 1-13. DOI: 10.1016/j.carbpol.2019.115612 Published online November 12, 2019. Hereinafter Maver.
8 CON of 18/090,647 filed December 29, 2022, has PRO 63/477,264 filed December 27, 2022, has PRO 63/295,076 filed December 30, 2021. Hereinafter App’091.
9 Michaelsen et. al. "The Effect of Digestion and Drug Load on Halofantrine Absorption from Self-nanoemulsifying Drug Delivery System (SNEDDS)" AAPS J. 2016, 18, 1, 180-186. DOI: 10.1208/s12248-015-9832-7. Hereinafter Michaelsen.
10 DIV of 18/680,463 filed May 31, 2024, CON of PCT/US2023/030238 filed August 15, 2023, PRO 63/398,480 filed August 16, 2022. Hereinafter App’411.
11 Nan et. al. "Evaluation of Carbamazepine (CBZ) Supersaturatable Self-Microemulsifying (S-SMEDDS) Formulation In-vitro and In-vivo" Iran J Pharm Res 2012, 11, 1, 257-264. PMID: 24250448. Hereinafter Nan.
12 CON of 18/090,647 (Abandoned) filed December 29, 2022, has PRO 63/477,264 filed December 27, 2022, has PRO 63/295,076 filed December 30, 2021. Hereinafter App’269.
13 CON of 17/321,928 (Abandoned), CON of 16/108,463 (Abandoned), CON of 15/400,087 (Abandoned), CON of 14/472,181 (Patented), CON of 13/138,282 (Abandoned), 371 of PCT/US2010/000170 filed January 22, 2010. Hereinafter App’900.