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 . Claims 4, 8, 11, 27-32, 34, 37 and 49-50 filed March 21, 2024 are currently pending. Claims 4 and 11 are independent claims.
Priority
Acknowledgement is made of the national stage entry of PCT/US2021/065290 filed 12/28/2021 which claims priority to U.S. Provisional Application 63131419 filed 12/29/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/09/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 30-32 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claim. See MPEP § 608.01(n).
In the present case, each of claims 30-32 depend upon claim 29, which is a multiple dependent claim, as claim 29 depends upon the methodology of claim 4 or in the alternative, claim 11. Accordingly, the claims have not been further treated on the merits.
Claim Rejections - 35 USC § 112-Paragraph A
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 4, 8, 11, 27-29, 34, 37 and 49-50 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. The courts have stated that, “To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”). Thus, an applicant complies with the written description requirement “by describing the invention, with all its claimed limitations, not that which makes it obvious,” and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 48 USPQ2d 1398.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated that, “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials.” Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) (“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...”) Regents of the University of California v. Eli Lilly & Co., 43 USPQe2d 1398.
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP § 2163. The MPEP does state that for a generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad generic. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include (1) level of skill and knowledge in the art, (2) partial structure, physical and/or chemical properties, (3) functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and (4) the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP § 2163. While all of the factors have been considered, a sufficient amount for a prima facie case are discussed below.
In the instant case, independent claim 4 is directed to the method of treating gastroparesis in a human subject in need thereof, comprising administering to the subject metopimazine, or a pharmaceutically acceptable salt thereof, in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal liver amidase. Additionally, independent claim 11 is also directed to a method of treating nausea associated with gastroparesis in a human subject in need thereof, comprising administering to the subject metopimazine, or a pharmaceutically acceptable salt thereof, in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal liver amidase.
(1) Partial structure: The claims do not provide any structure for the genus of “wherein the additional therapeutic agent is not metabolized by human microsomal liver amidase”. The genus is described by its function (e.g., an agent that is not metabolized by human microsomal liver amidase) without sufficient written description of its structure. There is no known or disclosed structure/function relationship for the metabolism of therapeutic agents that are not metabolized by human microsomal liver amidase. Moreover, the specification does not provide any definition to the genus nor structural blazemarks as to which agents lie inside the claimed genus and which agents are outside the purported genus.
As described in MPEP § 2163, for a generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP §2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. However, there are NO distinct species of any framework encompassed in claims 4, 8, 11, 27-29, 34, 37 and 49-50. In the working examples on pages 56-61 of the specification, said working embodiments provides a genus of compounds that neither share a similar structural framework nor comprise similar functionalities. The specification lists bupropion, dextromethorphan, diclofenac, midazolam, paclitaxel, phenacetin, testosterone, itraconazole, montelukast, quinidine, sulfaphenazole, benzydamine, bis(4-nitrophenyl) phosphate (BNPP), 7-ethoxycoumarin (7-EC), menadione, methimazole, phthalazine, and B nicotinamide adenine dinucleotide phosphate (NADPH, tetra sodium salt), Chlorzoxazone, 1-aminobenzotriazole (ABT), Coumarin, (S) Mephenytoin, (+)-benzylnirvanol, tranylcypromine and Furafylline.
From the working examples, it is unclear if any of these molecules are, or alternatively are not metabolized by human microsomal liver amidase, as the specification only exemplifies an in-vitro analysis of the metabolism of the claimed metopimazine with S9 liver amidase and the formation of the metabolite metopimazine-acid (MPZA) or other metabolites (MPZ-S or MPZ-H) (pages 56-61). The specification does not demonstrate any other compound with metopimazine that is not metabolized by human microsomal liver amidase. Applicant employs 1-ABT from the genus above as a pan cytochrome P450 (CYP) liver enzyme inhibitor to test the metabolic pathway of the claimed metopimazine. Applicant also employs coumarin as a CYP26A substrate, chlorzoxazone as a CYP2E substrate, midazolam as a CYP3A4 and CYP3A5 substrate, furafylline as a CYP1A2 inhibitor, itraconazole as a CYP3A4/5 inhibitor, quinine as a CYP2D6 inhibitor, benzylnirvinol as a CYP2C19 inhibitor, sulfaphenazole as a CYP2C9 inhibitor, montelukast as a CYP2C8 inhibitor and tranylcypromine as a CYP2B6 inhibitor (pages 57-58). As such, it is unclear from the compounds listed above, if any, lie inside the purported genus of “additional therapeutic agent not metabolized by human microsomal liver amidase”, and which agents lie outside the claimed genus.
As such, the embodiments in the claims do not provide descriptive support for the entire genus of agents claimed, as the agents within the genus described are not closely related in structure and the claims do not show the variance embraced by the genus.
(2) Physical and/or chemical properties and (3) Functional characteristics:
As recited above, the claims do not provide any structure for the genus of “wherein the additional therapeutic agent is not metabolized by human microsomal liver amidase”. The genus is described by its function (e.g., an agent that is not metabolized by human microsomal liver amidase) without sufficient written description its structure. There is no known or disclosed structure/function relationship for the metabolism of therapeutic agents that are not metabolized by human microsomal liver amidase. Further, there are no physical or chemical properties listed in the specification or claims for “agents that are not metabolized by human microsomal liver amidase”. Nor are there distinct functional characteristics provided, other than the specific metabolic pathway by which the agent is purportedly not metabolized by.
(4) Method of making the claimed invention:
As databases such as Kyoto Encyclopedia of Genes and Genomes (KEGG database) are used for pathway prediction methods and said database is manually curated with links to specific information about compounds, enzymes and genes. Datasets containing therapeutic agents run through the KEGG database are not 100% accurate on identifying the distinct metabolic pathway for the proposed therapeutic agent. Baranwal (Bioinformatic Vo. 36 pages 2547-2553 published online 12/26/2019) represents the state of the prior art. Baranwal discloses mapping small molecules to metabolic pathway classes utilizing the functional group analysis, using compounds of 11 identified pathway classes. Said methodology obtained an overall accuracy of 73% for the predictor of metabolic pathway classes (pages 2547-2548). However, said methodology was not extendable to compounds belonging to more than one pathway class (page 2548 left col.). None of the molecules assayed were predicted to not be metabolized by human microsomal liver amidase. As such, the method of making the claimed invention of administering a therapeutic agent wherein the therapeutic agent is not metabolized by human microsomal liver amidases would require an undue burden as there is no structure-function relationship, nor physical nor chemical properties to provide blazemarks for the purported genus, coupled with the knowledge that even employing a bioinformatic approach for predicting metabolic pathways still yields a high level of uncertainty.
As stated supra, the MPEP states that written description for a genus can be achieved by a representative number of species within a broad generic. It is unquestionable that the claims are broad and generic, with respect to all possible compounds encompassed by the claims. The possible structural variations are limitless. Although the claims may recite some functional characteristics, such as a distinct metabolic pathway in which the additional therapeutic agent is not metabolized by, the claims lack written description because there is no disclosure of a correlation between function and structure of the genus of “wherein the additional therapeutic agent is not metabolized by human microsomal liver amidase”. Moreover, as stated above, the specification lacks any structure-function relationship or physical or chemical properties to reflect the variance in the genus. Thus, the specification does not provide sufficient descriptive support for the myriad of compounds embraced by the claims.
The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”) Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 4, 8, 11, 27-29, 34, 37 and 49-50 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Camilleri (NEJM Vol. 356 pages 820-829. Published 2007), Merino (Metabolism Clinical and Experimental Vol. 113 pages 154352 published September 2020) and De Colle (WO2014/105655 published 07/03/2014).
Camilleri (NEJM Vol. 356 pages 820-829. Published 2007) teaches gastroparesis in insulin-dependent (type 1) diabetic patients. Camilleri teaches gastroparesis is a disorder defined by delayed gastric emptying and characterized by nausea, vomiting and other chronic debilitating symptoms that improves little over time. Camilleri teaches patients with diabetic gastroparesis may cause severe symptoms and result in nutritional compromise, impaired glucose control and a poor quality of life (page 820). Camilleri recommends antiemetic agents to provide relief for the symptoms (page 820-821).
Merino (Metabolism Clinical and Experimental Vol. 113 pages 154352 published September 2020) teaches the enzyme insulin degrading enzyme (IDE). Said enzyme is a zinc-metalloendopeptidase that degrades insulin and glucagon, and is primarily expressed in the cytoplasm of both insulin and non-responsive cell types. Merino teaches that insulin degrading enzyme plays a major role in hepatic insulin clearance, a physiological process that removes up to 80% of secreted insulin during its first pass through the liver (page 1).
The difference between the present claims and that of Camilleri and Merino is that neither Camilleri nor Merino specifically teach treating gastroparesis in a human subject comprising metopimazine to said subject.
De Colle (WO2014/105655 published 07/03/2014) teaches the method of treating gastroparesis and symptoms including nausea in a human subject in need thereof comprising administering a therapeutically effective amount of metopimazine ([0080]-[0082], [0099] claims 9-11, 14, 18-19). As evidenced by [00138], Formula (III) of De Colle is art-recognized as metopimazine. De Colle exemplifies the treatment of gastroparesis in an animal model wherein metopimazine significantly increased gastric emptying in a subject in need compared to a vehicle control ([0235], Figure 3).
De Colle further teaches that metopimazine is suitable to be administered with additional therapeutic agents, including agents for treatment of clinical syndromes associated with gastroparesis, such as diabetes. De Colle teaches that insulin is a suitable additional therapeutic to administer with metopimazine to treat the metabolic disorder ([00200]-[00204]).
Therefore, one of ordinary skill in the art of treating a type-1 insulin-dependent diabetic with gastroparesis as taught by Camilleri, knowing that insulin is not metabolized by human microsomal liver amidase but rather metabolized by insulin-degrading enzyme in the liver as taught by Merino, said skilled artisan would have found it prima facie obvious to treat said type-1 insulin-dependent diabetic with gastroparesis comprising administering a therapeutically effective amount of metopimazine with said insulin therapy in view of De Colle.
Motivation to administer metopimazine to treat gastroparesis in the type-1 insulin-dependent diabetic patient with gastroparesis logically flows from the fact that De Colle teaches that metopimazine is efficacious at treating gastroparesis and is suitable to be administered with insulin. Accordingly, said skilled artisan would have readily predicted that administration of insulin in combination with metopimazine would have treated gastroparesis in the type-1 insulin dependent diabetic patient and that the administered insulin would not have been metabolized by human microsomal liver amidase.
Regarding claim 28, acute administration of metopimazine is taught by De Colle ([00103]). Regarding claims 27, 29 and 37, treatment of chronic symptoms is taught, wherein metopimazine is administered for a duration of at least 12 weeks in a dose of at least 30 mg per day ([0034], [0099], [00103], [0197]). Said dose of at least 30 mg overlaps with the therapeutically effective amount embraced in claim 37. Applicant is reminded of MPEP 2144.05 wherein the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).
Regarding claim 49, oral administration of metopimazine as a capsule is embraced in the methodology of De Colle ([00178]-[00179], claims 21-23). Regarding claim 50, preparation and administration of metopimazine in its methanesulfonic acid form (mesylate) is also embodied in the teachings of De Colle ([0126]).
Regarding the limitation wherein metopimazine is administered to the subject two times per day, the optimum dosing cycle and frequency of administration of metopimazine to the type-1 diabetic patient experiencing gastroparesis would have been a matter well within the insight of one of ordinary skill in the art. Such a determination would have been made in accordance with a variety of factors, such as the route of administration, pharmacological considerations, such as activity, efficacy, pharmacokinetics and toxicology profiles of the combined regimen, as well as the age, weight, sex, diet and severity of the medical condition of the patient as described in [0196] and [0199] of De Colle. Thus, the dosing cycle and frequency of administration regimen that would have been employed would have varied widely and, in the absence of evidence to the contrary, the current claimed specific administration regimen is not seen to be inconsistent with one that would have been determined by the skilled artisan. Furthermore, absent and evidence demonstrating a patentable difference between the compositions administered and the criticality of the claimed frequency and dosing cycles, the determination of the optimum or workable frequency of administration given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)(”[W]here the general conditions of the claim are disclosed in the prior art, it is not inventive to discover the workable ranges by routine experimentation.”)
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.
Claims 4, 8, 11, 27-29, 37 and 49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 13-15 and 20 of U.S. Patent No. 9,132,134 in view of Camilleri (NEJM Vol. 356 pages 820-829. Published 2007), Merino (Metabolism Clinical and Experimental Vol. 113 pages 154352 published September 2020) and De Colle (WO2014/105655 published 07/03/2014).
Although the claims at issue are not identical, they are not patentably distinct from each other because of the following.
Claims 1-8, 13-15, 20 of U.S. Patent 9,132,134 are directed to treating gastroparesis in a human subject in need comprising administering a therapeutically effective amount of metopimazine to a subject in need. Claims 2-3 embrace administering said metopimazine for a duration of 7 days, which reads on the dosing strategy embraced within claim 29. Claim 5 reads on administering a dose of 30 mg or more, which overlaps with the therapeutically effective amount in claim 37. Applicant is reminded of MPEP 2144.05 wherein the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Claims 13-15 and 20 claim oral administration of metopimazine in a capsule form, which reads on the subject matter found in claim 49, while claim 8 is directed to administering said metopimazine in combination with an additional therapeutic agent.
The difference between the methodology embraced within claims 1-8, 13-15 and 20 of U.S. Patent 9,132,134 and that of the present claims is that claims 1-8, 13-15 and 20 of U.S. Patent 9,132,134 does not teach wherein the additional agent is an agent that is not metabolized by human microsomal liver amidase.
De Colle (WO2014/105655 published 07/03/2014) teaches the method of treating gastroparesis and said symptoms including nausea in a human subject in need thereof comprising administering a therapeutically effective amount of metopimazine ([0080]-[0082], [0099] claims 9-11, 14, 18-19). As evidenced by [00138], Formula (III) of De Colle is art-recognized as metopimazine. De Colle exemplifies the treatment of gastroparesis in an animal model wherein metopimazine significantly increased gastric emptying in a subject in need compared to a vehicle control ([0235], Figure 3).
De Colle further teaches that metopimazine is suitable to be administered with additional therapeutic agents, including agents for treatment of clinical syndromes associated with gastroparesis, such as diabetes. De Colle teaches that insulin is a suitable additional therapeutic to administer with metopimazine to treat the metabolic disorder ([00200]-[00204]).
Camilleri (NEJM Vol. 356 pages 820-829. Published 2007) teaches gastroparesis in insulin-dependent (type 1) diabetic patients. Camilleri teaches gastroparesis is a disorder defined by delayed gastric emptying and characterized by nausea, vomiting and other chronic debilitating symptoms that improves little over time. Camilleri teaches patients with diabetic gastroparesis may cause severe symptoms and result in nutritional compromise, impaired glucose control and a poor quality of life (page 820). Camilleri recommends antiemetic agents to provide relief for the symptoms (page 820-821).
Merino (Metabolism Clinical and Experimental Vol. 113 pages 154352 published September 2020) teaches the enzyme insulin degrading enzyme (IDE). Said enzyme is a zinc-metalloendopeptidase that degrades insulin and glucagon, and is primarily expressed in the cytoplasm of both insulin and non-responsive cell types. Merino teaches that insulin degrading enzyme plays a major role in hepatic insulin clearance, a physiological process that removes up to 80% of secreted insulin during its first pass through the liver (page 1).
Therefore, one of ordinary skill in the art knowing that administration of metopimazine is efficacious at treating gastroparesis in a human subject and is administered with an additional therapeutic agent as taught by claims 1-8, 13-15 and 20 of U.S. Patent 9,132,134 coupled with the knowledge that insulin therapy is suitable to administer with metopimazine to treat clinical symptoms associated with gastroparesis such as diabetes as taught by De Colle, said skilled artisan would have found it prima facie obvious to administer the therapeutic regimen of insulin and metopimazine to a type-1 insulin dependent diabetic patient experiencing gastroparesis in view of the combination of Camilleri and Moreno.
Motivation to administer metopimazine to treat gastroparesis in the type-1 insulin-dependent diabetic patient with gastroparesis logically flows from the fact that De Colle teaches that metopimazine is efficacious at treating clinical symptoms associated with gastroparesis such as diabetes and is suitable to be administered with insulin. Considering that insulin is not metabolized by human microsomal liver amidase but rather metabolized by insulin-degrading enzyme in the liver as taught by Merino, said skilled artisan would have readily predicted that administration of insulin in combination with metopimazine would have treated gastroparesis in the type-1 insulin dependent diabetic patient and that the administered insulin would not have been metabolized by human microsomal liver amidase.
Claims 4, 8, 11, 27-29, 37 and 49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-6, 9, 11, 13-15 of U.S. Patent 9,808,467 in view of Camilleri (NEJM Vol. 356 pages 820-829. Published 2007), Merino (Metabolism Clinical and Experimental Vol. 113 pages 154352 published September 2020) and De Colle (WO2014/105655 published 07/03/2014).
Although the claims at issue are not identical, they are not patentably distinct from each other because of the following.
Claims 1-2, 4-6, 9, 11, 13-15 of U.S. Patent 9,808,467 are directed to treating an enteric nervous system disorder in a human subject in need comprising administering a therapeutically effective amount of metopimazine to a subject in need. Claims 2, 4-6 embrace administering said metopimazine for a duration of 7 days, which reads on the dosing strategy embraced within claim 29. Claim 4 reads on administering a dose of 30 mg or more, which overlaps with the therapeutically effective amount in claim 37. Applicant is reminded of MPEP 2144.05 wherein the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Claims 13-15 and 20 claim oral administration of metopimazine in a capsule form, which reads on the subject matter found in claim 49, while claims 5-6 are directed to administering said metopimazine in combination with an additional therapeutic agent, including insulin.
The difference between the methodology embraced within claims 1-2, 4-6, 9, 11, 13-15 of U.S. Patent 9,808,467 and that of the present claims is that claims 1-2, 4-6, 9, 11, 13-15 of U.S. Patent 9,808,467 does not teach wherein the additional agent is an agent that is not metabolized by human microsomal liver amidase, nor do claims 1-2, 4-6, 9, 11, 13-15 of U.S. Patent 9,808,467 teach wherein the enteric nervous system disorder is gastroparesis.
De Colle (WO2014/105655 published 07/03/2014) teaches the method of treating gastroparesis and said symptoms including nausea in a human subject in need thereof comprising administering a therapeutically effective amount of metopimazine ([0080]-[0082], [0099] claims 9-11, 14, 18-19). De Colle teaches that gastroparesis is a species of enteric nervous system disorder (claims 17-18). As evidenced by [00138], Formula (III) of De Colle is art-recognized as metopimazine. De Colle exemplifies the treatment of gastroparesis in an animal model wherein metopimazine significantly increased gastric emptying in a subject in need compared to a vehicle control ([0235], Figure 3).
De Colle further teaches that metopimazine is suitable to be administered with additional therapeutic agents, including agents for treatment of clinical syndromes associated with gastroparesis, such as diabetes. De Colle teaches that insulin is a suitable additional therapeutic to administer with metopimazine to treat the metabolic disorder ([00200]-[00204]).
Camilleri (NEJM Vol. 356 pages 820-829. Published 2007) teaches gastroparesis in insulin-dependent (type 1) diabetic patients. Camilleri teaches gastroparesis is a disorder defined by delayed gastric emptying and characterized by nausea, vomiting and other chronic debilitating symptoms that improves little over time. Camilleri teaches patients with diabetic gastroparesis may cause severe symptoms and result in nutritional compromise, impaired glucose control and a poor quality of life (page 820). Camilleri recommends antiemetic agents to provide relief for the symptoms (page 820-821).
Merino (Metabolism Clinical and Experimental Vol. 113 pages 154352 published September 2020) teaches the enzyme insulin degrading enzyme (IDE). Said enzyme is a zinc-metalloendopeptidase that degrades insulin and glucagon, and is primarily expressed in the cytoplasm of both insulin and non-responsive cell types. Merino teaches that insulin degrading enzyme plays a major role in hepatic insulin clearance, a physiological process that removes up to 80% of secreted insulin during its first pass through the liver (page 1).
Therefore, one of ordinary skill in the art knowing that administration of metopimazine in combination with insulin is efficacious at treating enteric nervous system disorders in a subject in need gastroparesis in a human subject as taught by claims1-2, 4-6, 9, 11, 13-15 of U.S. Patent 9,808,467 coupled with the knowledge that De Colle teaches that gastroparesis is a species of enteric nervous system disorder, said skilled artisan would have found it prima facie obvious to administer the therapeutic regimen of insulin and metopimazine to a type-1 insulin dependent diabetic patient experiencing gastroparesis in view of the combination of Camilleri and Moreno, arriving at the instantly claimed methodology.
Motivation to administer metopimazine to treat gastroparesis in the type-1 insulin-dependent diabetic patient with gastroparesis logically flows from the fact that De Colle teaches that metopimazine is efficacious at treating clinical symptoms associated with gastroparesis such as diabetes and is suitable to be administered with insulin. Considering that insulin is not metabolized by human microsomal liver amidase but rather metabolized by insulin-degrading enzyme in the liver as taught by Merino, said skilled artisan would have readily predicted that administration of insulin in combination with metopimazine would have treated enteric nervous system disorder of gastroparesis in the type-1 insulin dependent diabetic patient and that the administered insulin would not have been metabolized by human microsomal liver amidase.
Claims 4, 8, 11, 27-29, 34, 37 and 49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10, 12 and 15 of U.S. Patent 11,147,820 in view of Camilleri (NEJM Vol. 356 pages 820-829. Published 2007), Merino (Metabolism Clinical and Experimental Vol. 113 pages 154352 published September 2020) and De Colle (WO2014/105655 published 07/03/2014).
Although the claims at issue are not identical, they are not patentably distinct from each other because of the following.
Claims 1-10, 12, and 15 are directed to treating gastroparesis and symptoms thereof such as nausea in a human subject in need comprising administering a therapeutically effective amount of metopimazine to a subject in need. Claims 5-10 embrace administering said metopimazine for a duration of 7 days, which reads on the dosing strategy embraced within claim 29. Claim 15 reads on administering a dose of 20 mg or more, which overlaps with the therapeutically effective amount in claim 37. Applicant is reminded of MPEP 2144.05 wherein the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Claims 12 is directed to administering metopimazine two times a day, which reads on the frequency of administration found in claim 34.
The difference between the methodology embraced within claims 1-10, 12 and 15 of U.S. Patent 11,147,820 and that of the present claims is that claims 1-10, 12 and 15 of U.S. Patent 11,147,820 does not teach administering metopimazine with an additional therapeutic agent, wherein the additional agent is an agent that is not metabolized by human microsomal liver amidase.
De Colle (WO2014/105655 published 07/03/2014) teaches the method of treating gastroparesis and said symptoms including nausea in a human subject in need thereof comprising administering a therapeutically effective amount of metopimazine ([0080]-[0082], [0099] claims 9-11, 14, 18-19). As evidenced by [00138], Formula (III) of De Colle is art-recognized as metopimazine. De Colle exemplifies the treatment of gastroparesis in an animal model wherein metopimazine significantly increased gastric emptying in a subject in need compared to a vehicle control ([0235], Figure 3).
De Colle further teaches that metopimazine is suitable to be administered with additional therapeutic agents, including agents for treatment of clinical syndromes associated with gastroparesis, such as diabetes. De Colle teaches that insulin is a suitable additional therapeutic to administer with metopimazine to treat the metabolic disorder ([00200]-[00204]).
Camilleri (NEJM Vol. 356 pages 820-829. Published 2007) teaches gastroparesis in insulin-dependent (type 1) diabetic patients. Camilleri teaches gastroparesis is a disorder defined by delayed gastric emptying and characterized by nausea, vomiting and other chronic debilitating symptoms that improves little over time. Camilleri teaches patients with diabetic gastroparesis may cause severe symptoms and result in nutritional compromise, impaired glucose control and a poor quality of life (page 820). Camilleri recommends antiemetic agents to provide relief for the symptoms (page 820-821).
Merino (Metabolism Clinical and Experimental Vol. 113 pages 154352 published September 2020) teaches the enzyme insulin degrading enzyme (IDE). Said enzyme is a zinc-metalloendopeptidase that degrades insulin and glucagon, and is primarily expressed in the cytoplasm of both insulin and non-responsive cell types. Merino teaches that insulin degrading enzyme plays a major role in hepatic insulin clearance, a physiological process that removes up to 80% of secreted insulin during its first pass through the liver (page 1).
Therefore, one of ordinary skill in the art knowing that administration of metopimazine is efficacious at treating gastroparesis and symptoms thereof such as nausea in a human subject thereof as taught in claims 1-10, 12 and 15 of U.S. Patent 11,147,820 coupled with the knowledge that insulin therapy is suitable to administer with metopimazine to treat clinical symptoms associated with gastroparesis such as diabetes as taught by De Colle, said skilled artisan would have found it prima facie obvious to administer the therapeutic regimen of insulin and metopimazine to a type-1 insulin dependent diabetic patient experiencing gastroparesis in view of the combination of Camilleri and Moreno.
Motivation to administer metopimazine to treat gastroparesis in the type-1 insulin-dependent diabetic patient with gastroparesis logically flows from the fact that De Colle teaches that metopimazine is efficacious at treating clinical symptoms associated with gastroparesis such as diabetes and is suitable to be administered with insulin. Considering that insulin is not metabolized by human microsomal liver amidase but rather metabolized by insulin-degrading enzyme in the liver as taught by Merino, said skilled artisan would have readily predicted that administration of insulin in combination with metopimazine would have treated gastroparesis in the type-1 insulin dependent diabetic patient and that the administered insulin would not have been metabolized by human microsomal liver amidase.
Conclusion
In view of the rejections set forth above, no claim is allowed.
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/GEORGE W KOSTURKO/Examiner, Art Unit 1621