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 .
Status of the Claims
Currently, claims 1-21 are pending in the instant application.
Priority
The instant application is a DIV of application 17/163,010 filed on 01/29/2021. Said parent application 17/163,010 has issued as US patent No. 12109202.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/08/2024 and 01/28/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112 – Second Paragraph
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.
Claims 18 and 20 are 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.
Claims 18 and 20 are indefinite for reciting “the quaternary ammonium anti-cholinergic muscarinic receptor antagonist”, because a person of ordinary skill in the art would not reasonably understand the metes and bounds of the claim. Parent claim 17 does not recite a “quaternary ammonium anti-cholinergic muscarinic receptor antagonist”, but a “quaternary ammonium antimuscarinic compound”. Accordingly, the instant claims provide improper antecedence to claim 17.
Claim 20 is indefinite for reciting “the acetyl-cholinesterase inhibitor”, because a person of ordinary skill in the art would not reasonably understand the metes and bounds of the claim. Claim 17 recites a “cholinesterase inhibitor” and not an “acetyl-cholinesterase inhibitor. Accordingly, the instant claim provides improper antecedence to claim 17.
Claim Rejections - 35 USC § 112 – First Paragraph
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.
Claim 1-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the treatment of dementia with Lewy bodies using a combination of rivastigmine and glycopyrrolate, does not reasonably provide enablement for improvement in cognitive function in a human suffering from any neurodegenerative cognitive disorder with any combination of cholinesterase inhibitor and quaternary ammonium antimuscarinic compound (QAAMC). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make use of the invention commensurate in scope with these claims.
Per MPEP 1264.08: All questions of enablement are evaluated against the claimed subject matter. When considering whether claims in a utility patent application or patent are enabled, USPTO personnel will use the Wands factors to ascertain whether the amount of experimentation required to enable the full scope of the claimed invention is reasonable. The propriety of a rejection based upon the scope of a claim relative to the scope of the enablement concerns (1) how broad the claim is with respect to the disclosure and (2) whether one skilled in the art could make and use the entire scope of the claimed invention without undue experimentation.
Per re Wands the factors include the following:
The breadth of the claims
The nature of the invention
The state of the prior art
The level of one of ordinary skill
The level of predictability in the art
The amount of direction provided by the inventor
The existence of working examples
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
(A) The Breadth of the claims
Claim 1 recites a method for improving cognitive function in a human suffering from a “neurodegenerative cognitive disorder” wherein the method comprises administering a combination of a “cholinesterase inhibitor” and a “quaternary ammonium antimuscarinic compound. Likewise, claim 17 recites a method for improving cognitive function in a human suffering from a “neurodegenerative cognitive disorder” wherein the method comprises introducing a “cholinesterase inhibitor” and “quaternary ammonium compound” to the body of a human. In both of these claims, the breadth encompasses an innumerable number of diseases/disorders having differing etiologies and pathologies to which cholinesterase inhibitors and QAAMCs may provide differing effects and efficacies. Claims dependent upon claims 1 and 17 do not individually ameliorate the overly wide breadth established the parent claims.
(B), (C), (D), (E) The nature of the invention, the state of the prior art, the level of one of ordinary skill, and the level of predictability in the art
The claims are directed towards the treatment of neurodegenerative cognitive disorders by combination dosing of cholinesterase inhibitors and QAAMCs at varying rates of release. With regards to the diseases/disorders, the neurodegenerative cognitive disorders are a highly complex category of conditions, not often unified by a single traceable cause. For example, Tan (BioMed Research International Volume 2015, Article ID 272630) indicates neurodegeneration occurs in a plethora of different conditions, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), and is considered multifactorial (page 1)1. Tan further indicates that extent of contribution of such factors to neurodegeneration is also a currently debated matter. Accordingly, the predictability of the blanket effect of treatment on all neurodegenerative cognitive disorders appears relatively low. A person of ordinary skill in the art in regards to the relevant subject matter would require experience in the fields of chemistry, pharmaceuticals, and neurodegenerative disorders.
(F), (G), (H) The amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed
Looking towards Applicant’s specification for guidance, no matter is provided which specifically directs a person of ordinary skill in the art to be able to treat any and all forms of neurodegenerative cognitive disorders using a combination of any cholinesterase inhibitor and QAAMC. However, Applicant does provide working examples wherein patients with Lewy body dementia are treated using a combination rivastigmine and glycopyrrolate. In specification page 152, Applicant indicates that Fig. 4 depicts resulting data of administering a co-formulation comprising rivastigmine and glycopyrrolate. Keeping in mind the broad range of differing etiologies and pathologies encompassed by neurodegenerative cognitive disorders, the examples provided by Applicant cannot be considered as sufficiently representative to claim improvement in cognitive function in across all such disorders by administration of a broad range of cholinesterase inhibitors and QAAMCs. The amount of experimentation needed to cover the broad scope of the claims would entail the testing of a myriad of compound combinations across a wide spectrum etiologically differing disorders and diseases. Furthermore, in specific regards to claim 17, the recitation of “the first rate is different than the second rate”, would require a further undue amount of experimentation with regards to adjusting rates of absorption of the component actives.
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.
Claim(s) 17, and 19-21is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rich (US 20130172379 A1).
Claim 17 recites a method of improving cognitive function in a human suffering from a neurodegenerative cognitive disorder, wherein the method comprises:
introducing a therapeutic amount of 2-8 mg of a quaternary ammonium antimuscarinic compound into a body of a human at a first initial time;
introducing a therapeutic amount of 3-48 mg of a cholinesterase inhibitor into the body of the human at a second initial time;
releasing the therapeutic amount of 2-8 mg of the quaternary ammonium antimuscarinic compound into the body of the human at a first rate;
and releasing the therapeutic amount of 3-48 mg of the cholinesterase inhibitor into the body of the human at a second rate, wherein the first initial time is the same as the second initial time and the first rate is different than the second rate.
Rich teaches a method of improving cognitive function in a patient suffering from Lewy body dementia, wherein the patient is administered rivastigmine (a cholinesterase inhibitor) and glycopyrrolate (a QAAM). More specifically, Rich discloses an example wherein a patient is administered a 19 mg dose of rivastigmine transdermally alongside a 2 mg twice daily dose of glycopyrrolate (specification [0107])3. As the rivastigmine is administered transdermally and the glycopyrrolate is administered orally, the two compounds would inherently differ in release rate due to differing administration routes (i.e., systemic vs. parenteral). The results of said administration over the dosing duration of 36 months revealed MMSE scores higher than expected values, indicating an improvement in cognitive function (specification [0108])4. Expected MMSE score vs the actual MMSE score for said patient is depicted in the graph below (Fig. 2):
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Claim 18 further limits the method of claim 17 wherein the amount of QAAM receptor antagonist is administered orally, intravenously, subcutaneously, or intramuscularly.
Rich teaches the administration of glycopyrrolate orally.
Claim 19 further limits the method of claim 17 wherein the cholinesterase inhibitor is administered orally or transdermally.
Rich teaches the transdermal administration of rivastigmine.
Claim 21 further limits the method of claim 17 wherein the QAAM compound is glycopyrrolate or trospium.
Rich teaches the use of glycopyrrolate.
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.
Claim(s) 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rich (previously referenced) in view of Chase (US 20190365736 A1).).
Claim 20 further limits the method of claim 17 wherein the QAAM is introduced into the body in a rapidly dissolving gelatin capsule, and the therapeutic amount of the acetyl-cholinesterase inhibitor is introduced into the body of a human in an enclosed acid resistant hydroxypropylmethylcellulose capsule configured for delayed release.
As discussed previously, Rich teaches the method of claim 17. Rich does not explicitly teach the use of a gelatin capsule in the administration of the QAAM or the use of an acid resistant HPMC capsule for administering the cholinesterase inhibitor. However, it would have been obvious for a person of ordinary skill to apply such carrier to the method of Rich because Chase teaches such carriers for the administration of cholinesterase inhibitors and non-selective peripheral anticholinergic agents (nsPAChA), and there would have been reasonable expectation that such compositions would be effective in treating neurodegenerative disorders.
Chase teaches compositions comprising cholinesterase inhibitors and nsPAChAs for treating neurodegenerative disorders. More specifically, Chase teaches compositions comprising a component (a), and component (b) wherein component (a) further comprises an nsPAChA, and component (b) comprises a cholinesterase inhibitor (specification [0568]-[0569])5. nsPAChAs appear to include compounds such as glycopyrronium and trospium, while cholinesterase inhibitors include compounds such as rivastigmine. Chase further indicates that both components can be formulated as either instant release (IR) or extended release (ER) forms according to known technologies (specification [0575])6. Such technologies including gelatin capsules for oral administration (specification [0576])7 and hydroxypropylmethylcellulose for controlled release (specification [0586])8.
Given that both Rich and Chase are directed to the treatment of neurodegenerative disorders by administering cholinesterase inhibitors, and glycopyrrolate or trospium, and that Chase makes reasonable suggestions for the administration of cholinesterase inhibitors as an extended or controlled release dosing form, it would have been prima facie obvious for a person of ordinary skill in the art to be able to apply such dosing forms to the methods of Rich because there would be a reasonable expectation that such dosing forms would be effective in treating neurodegenerative cognitive disorders.
Allowable Subject Matter
While the claims of the instant application are not in condition for allowance, the claims at least contain allowable subject matter. More specifically in regards to treating or improving cognitive function in patients suffering from Lewy body dementia by administering a composition comprising rivastigmine and glycopyrrolate, wherein the glycopyrrolate is provided in a first drug delivery element and rivastigmine is provided in a second drug delivery element, wherein the first drug delivery element is formulated for a faster rate of absorption than the second drug delivery element.
The closest prior art found are Rich (US 20130172379 A1) and Chase (US 20190365736 A1).
Rich teaches composition comprising quaternary anticholinergic muscarinic receptor antagonists (QAAM) and acetylcholine esterase inhibitors, and methods of use thereof for treating cognitive impairment (specification [0036])9. Of particular relevance to the instant claims, Rich provides an example wherein patients with Lewy body dementia are administered rivastigmine and glycopyrrolate. Rich provides an example wherein a patient suffering from Lewy body dementia is administered transdermal rivastigmine once daily in an amount of 19 mg/day in combination with glycopyrrolate orally in an amount of 2 mg two times per day (specification [0107])10. The example of Rich meets the limitations of claim 1 regarding administering a QAAM and cholinesterase inhibitor in separate drug delivery elements, wherein the absorption rate of the QAAM element is faster than that of the cholinesterase inhibitor element (due to differences in administration route). Rich however, does not make mention of dosing regimen being timed with regards to food intake.
Chase teaches compositions comprising cholinesterase inhibitors and non-selective peripheral anticholinergic agents (nsPAChA), and uses thereof in treating neurodegenerative disease. It appears that nsPAChA compounds are not defined as being the same as QAAMs, but overlap in the cases of glycopyrronium and trospium. Chase provides a specified embodiment of their gelatin capsule compositions comprising a component (a) and component (c), wherein component (a) is an instant release tablet comprising glycopyrronium bromide, and wherein component (c) is an instant release tablet comprising rivastigmine (specification [0746])11. While Chase does indicate that the components of their compositions may be configured for instant release or extended release, Chase does not appear to provide specific motivation for the use of extended release cholinesterase inhibitors when in combination with glycopyrronium or trospium.
Conclusion
Claims 1-21 are rejected.
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/ERIC TRAN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 “Neurodegeneration refers to the progressive loss of structure or function of neurons and it can lead to devastating neurological conditions such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). Neurodegeneration is frequently multifactorial in origin though aging and genetic and environmental factors are thought to play a significant role. The relative contribution of genes and environmental factors has been debated. For AD and PD, both familial (monogenic and complex inheritance) and sporadic forms exist while some like HD are purely genetic in nature.”
2 “Fig. 4 exhibits the steady state blood serum rivastigmine levels in patients 3001, 3003, 3005, 3007, 3009 that have dementia with Lewy bodies and had demonstrated a reduction in the rate of cognitive decline over years with combined rivastigmine and glycopyrrolate administered separately. These subjects did not display adverse effects despite high doses of rivastigmine - 36-42 mg/day orally, and 39.9 mg/day transdermally. Patient 3009 was administered two co-formulated capsules of 0.5 mg glycopyrrolate and 4.5 mg glycopyrrolate four times per day, one hour before eating, for a daily dose of rivastigmine of 36 mg. Based upon the concentration-time curves, it can be derived that the co-formulation can maintain a similar concentration of rivastigmine throughout the dosing interval.”
3 “A L was a 65 year old man with one year of symptoms of dementia with Lewy Bodies prior to the combination treatment. A L was treated with 19 mg/day of rivastigmine transdermally once daily in combination with 2 mg glycopyrrolate two times a day.”
4 “FIG. 2 compares the expected (200) results of the MMSE test based on A L's MMSE score at the beginning of his treatment for dementia with Lewy Bodies with the actual (250) MMSE test results for patient A L. The x-axis shows the number of months of treatment. When patient A L began treatment, his MMSE score was 27. A L's score remained between 26 and 30 during the 36 month period shown in the figure. In comparison, the expected MMSE score at approximately 21 months is 15, and at the 35 month mark is less than 10. This is a remarkable improvement in cognitive function, and indicates that the combination treatment has dramatically slowed the progression of the disease.”
5 “(a) a nsPAChA selected from the group consisting of solifenacin, pharmaceutically acceptable salts of solifenacin, propiverine, pharmaceutically acceptable salts of propiverine, trospium quaternary salts, clidinium quaternary salts, benzilonium quaternary salts and glycopyrronium quaternary salts… (b) an AChEI selected from the group consisting of (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one (donepezil) and pharmaceutically acceptable salts thereof, (S)—N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate (rivastigmine) and pharmaceutically acceptable salts thereof, 4aS,6R,8aS-3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydroxy-6H-benzofuro[3a,3,2-e,f]benzazepin-6-ol (galantamine) and pharmaceutically acceptable salts thereof, and (1R,9S,13E)-1-amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,10-trien-5-one (huperzine A), in an amount of from 2.5 to 7 times the maximum amount contained in the commercial products for the treatment of Alzheimer type dementia.”
6 “Component (a) and Component (b) are formulated with conventional pharmaceutical carriers in known formulations for oral use wherein said components are mixed together or separated, for example in two tablets introduced in a capsule or in a two-compartment capsule or in a multilayer (di-layer) tablet wherein the two components are both in IR or in ER form or one of the two components is in IR form and the other is in ER form, according to known technologies.”
7 “The pharmaceutical carriers and vehicles are those commonly used for the preparation of compositions for oral, buccal and parenteral, in particular transdermal, administration. Appropriate unit forms comprise the oral forms such as tablets, soft or hard gelatin capsules”
8 “The association nsPAChA/AChEI may be formulated in tablets in which one or both of the two components is in controlled-release formulation, for example as a dispersion of said component in hydroxypropyl methyl cellulose or in a film-coated microgranule.”
9 “A method administers quaternary ammonium anti-cholinergic muscarinic receptor antagonists in combination with acetyl-cholinesterase inhibitors to treat cognitive impairment and/or acute delirium.”
10 “A L was a 65 year old man with one year of symptoms of dementia with Lewy Bodies prior to the combination treatment. A L was treated with 19 mg/day of rivastigmine transdermally once daily in combination with 2 mg glycopyrrolate two times a day.”
11 “Another advantageous composition according to this embodiment consists of soft or hard gelatin capsules each containing [0747] Tablet A comprising from 2 mg to 16 mg of glycopyrrolium bromide, as Component (a), in admixture with a pharmaceutical carrier in a IR formulation; and [0748] Tablet B, comprising from 25 mg to 42 mg of rivastigmine (as hydrogen tartrate); as Component (b), in admixture with a pharmaceutical carrier in an IR-formulation.”
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