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 .
Priority
The instant application, filed 04/29/2024, is the national stage entry of International Application No PCT/CN2021/126593, filed 10/27/2021. The examiner notes for the record that 30 months from the filing of the international application fell on a Saturday, that the instant application was filed on the next business day, and that international application, which published in Chinese, does not have a priority claim
Information Disclosure Statement
The Information Disclosure Statement filed on 10/31/2024, is acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the Information Disclosure Statement has been considered.
Status of Claims
Claims 1-16 were originally presented on 04/29/2024. The preliminary amendments to the claims also filed on 04/29/2024 are acknowledged and entered. Claims 1-16 were cancelled and claims 17-36 were added.
Accordingly, Claims 17-36 are pending.
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.
Rejection Statement
Claims 17-36 are rejected under 35 U.S.C. 103 as being unpatentable over WO’6721 in view of Li 20072 as evidenced by Carlier 1999 B3C, 3 Friedman 2015,4 and CN’051.5
The rejection will follow after the below discussion of the invention and background.
Discussion of the Invention and Background
The instant claims are drawn to Applicant’s reports that certain inhibitors of acetylcholinesterase (“AChE”) may be effective for treating osteoarthritis (“OA”) and related conditions. AChE inhibitors, in part, prevent breakdown of acetylcholine (“ACh”), a neurotransmitter, and are typically indicated for the treatment of Alzheimer’s disease.
The examiner generally interprets the claims as being drawn to new indications for this class of drugs/compounds, i.e., AChE inhibitors.
The actives administered in various in vitro studies Applicant discloses are shown below. Donepezil has been marketed under the trade name Aricept. Galantamine has been marketed as Razadyne. Compounds B(3)-C, B(7)-C, A10E, and E12E, are either homodimers or heterodimers of tacrine (marketed originally as Cognex) and huperzine A (a plant extract), each of which are AChE inhibitors. Applicant admits that all of these compounds were known in the art, as discussed below.6
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A10E
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E12E
Applicant makes reference to Li 2007, which teaches at 391, Figure 8, the B(7)-C, A10E, and E12E compounds, as shown below, and reports on their AChE inhibition assays throughout. In Li 2007, E12E is designated the same, and A10E is designated compound 6g, which is also called “Hupyridone(10)-tacrine”.
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Li 2007 at 391, Figure 8.
Several claims (e.g., 26 and 36) are drawn to a particular tacrine/huperzine dimer, which is also discussed in Li 2007 at 390, excerpted below (see compound 7). The examiner notes that Applicant appears to provide no data for these claims. I.e., there appear to be no in vitro, in vivo, or even in silico data for this compound, and the claims rest on the theory of AChE inhibition:
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Li 2007 at 390.
The final compound Applicant studied is the B(3)-C compound, which the examiner did not find in Li 2007 directly. Nevertheless it does appear in citation 24 of Li 2007, to Carlier 1999 B3C. Carlier 1999 B3C designates this compound A3A, which it described as follows (left column below, is page 352 to give representative structure relative to tacrine (abbreviated at TCA), right is page 353 that discusses shortening the linker length and its effects on selectivity for AChE and BChE) :
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Carlier 1999 B3C at 352 (left) and 353 (right). The THA acronym means tacrine.
The AChE/BChE inhibition selectivity by the tacrine dimers was known to be a function of the linker length. See Carlier 1999 B3C at 354, Figure 1:
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Carlier 1999 B3C at 354, Figure 1.
B(3)-C, also called B3C was worked up for its neuroprotective effects. See, e.g., Hu 2015,7 at Abstract, reproduced below, which is helpful as it introduces the α7-nAChR signal pathway:
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Hu 2015 at Abstract.
Hu 20138 at 469, Table 1, teaches some of B3C’s other effects outside of AChE inhibition:
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Hu 2013 at 469, Table 1.
As further background, Schubert 20129 teaches that α7-nAChR is expressed in the synovial tissue of patients with OA:
In our study α7-nAChR was expressed in synovial tissue of RA as well as OA. The α7-nAChR receptor exhibits an out-standing function for the anti-inflammatory cholinergic pathway (Wang et al., 2003). Wang et al. (2003) showed that ACh binds to α7-nAChR on macrophages and reduces the production of pro-inflammatory cytokines such as TNFα, IL-1, and IL-6 and IL-18. The α7-nAChR has been detected in several studies in the synovial membrane of RA patients. Waldburger and Firestein (2009) observed α7-nAChR in the fibroblast-like cells of synovial tissue (F-cells) in vivo and in vitro where they could show that inhibition of α7-nAChR leads to an increase in the release of pro-inflammatory cytokines. Stimulation of α7-nAChR by selective synthetic agonists as well as by administration of nicotine reduced the amount of pro-inflammatory cytokines (Waldburger et al., 2008, van Maanen et al., 2009). In line with these results van Maanen et al. (2010) observed an increase in pro-inflammatory cytokines in α7-nAChR knockout (KO) mice with experimentally induced arthritis. Also using α7-nAChR KO mice and the same collagen-II induced murine model of RA, Westman et al. (2010) observed a significantly milder arthritis and less cartilage destruction, demonstrating that this is a controversial field and additional studies are necessary to clarify the impact of α7-nAChR in the development of RA.…
Schubert 2012 at 1051-1052.
As further background, Lv 202110 teaches the cholinergic anti-inflammatory pathway (“CAP”) at Abstract, wherein ACh serves a central role in the immune system:
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Lv 2021 at Abstract.
Lv 2021 teaches the role of the CAP pathway in rheumatoid arthritis, osteoarthritis, and spondyloarthropathies, such as ankylosing spondylitis, reactive arthritis, psoriatic arthritis, enteropathic arthritis, and undifferentiated spondyloarthropathy throughout. Lv 2021 at 3, Figure 1 is helpful to visualize the CAP pathway and the roles of neuronal and non-neuronal ACh, and the α7-nAChR signal pathway:
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Lv 2021 at 3, Figure 1.
For more background, Zhang 201411 teaches a study of donepezil in the context of OA. See Zhang 2014 at Abstract:
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Zhang 2014 at Abstract.
Zhang 2014 also suggests the use of donepezil in the treatment of osteoarthritis:
DP is a centrally acting reversible acetylcholinesterase inhibitor, the main therapeutic use of which is in the palliative treatment of Alzheimer’s disease (AD). However, the precise mechanism of activity of DP is still unclear. Our results of examination in human chondrocytes in vitro indicated that the DP suppresses TNF-α-mediated the induction of MMP-13 occurred through inactivating STAT1/IRF-1, thereby preventing collagen type II degradation, suggesting a potential use of DP in OA.
Zhang 2014 at 116-117.
Further as background, Kandil 202012 teaches the use of a galantamine patch for rheumatoid arthritis, and at page 1000 discusses the author Gowayed and his work in the field. Citation 31 in the below excerpt is to a patent from Snorrason and Murray. Kandil 2020 at 1000 in the excerpt below further discusses the inflammatory cytokines found in serum samples from OA patients:
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Kandil 2020 at 1000.
Turning to the Gowayed papers13 referenced above, they discuss the role of α7-nAChR in arthritis, using galantamine to control inflammation in various rat models of arthritis. The online copies of two of the papers are also attached hereto, which provide graphical abstracts that are helpful to understand these pathways.
See, e.g., Gowayed 2019 at Graphical Abstract:
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Gowayed 2019 at Graphical Abstract.
See also, e.g., Gowayed 2020 at Graphical Abstract:
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Gowayed 2020 at Graphical Abstract.
Gowayed began studying galantamine in models of arthritis because: “The curious observation that patients suffering from RA had experienced a marked improvement of their symptoms upon treatment with galantamine (Snorrason and Murray, 2002), made up the idea of the present study.” See Gowayed 2015 at 548 (emphasis added). For an example of Gowayed’ s initial findings, see Gowayed 2015 at 552, Fig. 4 and Table 2:
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Gowayed 2015 at 552, Fig. 4 and Table 2.
The “curious observation” noted in Gowayed 2015 of Snorrason and Murray, 2002, is discussed in the following rejection of the claims.
Claims 17-36 Obvious over WO’672 in view of Li 2007 as evidenced by Carlier 1999 B3C, Friedman 2015, and CN’051
The discussion of Li 2007 as evidenced by Carlier 1999 B3C in the background section is incorporated herein.
WO’672 at 6-7 teaches “a method of treating or preventing arthritic disorders, including osteoarthritis, rheumatoid arthritis and other rheumatoid diseases …, said method comprising administering to a patient in need thereof an effective amount of a cholinesterase inhibitor”, and that “preferred cholinesterase inhibitors for use according to the invention are acetylcholinesterase inhibitors”.
WO’672 at 5-6 explains that the inventors discovered, in the treatment of patients with chronic fatigue syndrome, that there was “a considerable acetylcholinesterase activity” in the patients that also had rheumatological conditions, including osteoarthritis.
The invention is based on discoveries made in connection with the treatment of patients for other conditions, e.g. chronic fatigue syndrome.
Surprisingly, it was found that patients who, in addition to fibromyalgia or chronic fatigue syndrome, suffered from osteoarthritis or rheumatoid arthritis, had improvement of their arthritis symptoms. Thus, ten patients with rheumatoid arthritis were treated with galantamine. The purpose of the treatment was to treat their fatigue syndrome resulting from their rheumatoid arthritis. However, it was found that not only did the ten patients improve with respect to their fatigue syndrome, but also in the symptoms of their rheumatoid arthritis condition itself. They had less articular pain and the inflammatory process was less active (as evidenced by less swollen and less painful joints) while they were on treatment with galantamine. In other studies, reported in detail below, patients suffering from rheumatoid arthritis, osteoarthritis and other rheumatoid diseases, respectively, experienced marked improvements of their condition, e.g. with respect to tiredness, pain, stiffness and grip strength, upon treatment with galantamine .
It was also found by direct measurement that there is a considerable acetylcholinesterase activity in the synovial fluid of patients with rheumatological conditions. This finding is new and may shed light on the clinical observations with galantamine in rheumatological patients as this acetylcholinesterase activity is believed to exert a proteolytic activity in the synovial fluid of these patients and may be directly related to tissue damage seen in both rheumatoid diseases and in osteoarthritis.
WO’672 at 5-6.
See also, WO’672 at 18, Table 2, providing levels of acetylcholinesterase activity in representative patient synovial fluid taken from an affected joint:
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WO’672 at 18, Table 2.
See also, WO’672 at 19-23, wherein as an exemplified embodiment of its methods, galantamine was administered to patients with OA, RA, and other forms of arthritis. See also, WO’672 at 7, teaching that “tacrine and tacrine analogs”, “huperazine”, “donepezil”, and other related compounds work in this treatment protocol.
Accordingly, the examiner finds, regarding claims 17-26, that WO’672 teaches a method of a method of treating or preventing arthritic disorders, including osteoarthritis, rheumatoid arthritis and other rheumatoid diseases, said method comprising administering to a patient in need thereof an effective amount of an acetylcholinesterase inhibitor.
Moreover, regarding claims 27-36, WO’672 teaches the use of a pharmaceutically acceptable cholinesterase inhibitor or a pro-drug thereof in the manufacture of a medicament for combating diseases associated with proteolytic enzyme activity. The disease is selected from osteoarthritis, rheumatoid arthritis and other forms of arthritis. The cholinesterase inhibitor is an acetyl cholinesterase inhibitor. The cholinesterase inhibitor can be selected from tacrine and tacrine analogues, huperazine, donepezil, and galantamine. Specifically, also disclosed is the use of galantamine or a salt thereof in the manufacture of a medicament for combating osteoarthritis, rheumatoid arthritis or other forms of arthritis (see claims 1, 6, 7, 10, 11 and 32). The medicaments may comprise pharmaceutically acceptable carriers (WO’672 at 11-12), and general dosages by “injection”, or preferred “oral and transdermal administration” depend upon the “individual patient and may be determined by the medical practitioner based on individual circumstances”. WO’672 at 12. The examiner interprets these medicament as analogous to the claimed pharmaceutical compositions.
Therefore, while WO’672 explicitly teaches tacrine and tacrine analogues, huperazine, donepezil, and galantamine (claims 17-19 and 27-29), it does not appear to explicitly teach dimeric acetylcholinesterase inhibitors, because many of the dimeric acetylcholinesterase inhibitors had not been invented yet. These dimeric acetylcholinesterase inhibitors are encompassed by method claims 17, 18, and 20-26, and composition claims 27, 28, and 30-36.
However, Li 2007 as evidenced by Carlier 1999 B3C teaches the that the dimeric compounds B(3)-C and B(7)-C,14 A10E,15 E12E,16 and compound 7,17 are acetylcholinesterase inhibitors.
One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in treating or preventing arthritic disorders, including osteoarthritis, rheumatoid arthritis and other rheumatoid diseases, by administering the compounds B(3)-C, B(7)-C, A10E, E12E, or compound 7 in effective amounts, because WO’672 teaches that effective amounts of acetylcholinesterase inhibitors may be used in a method of treating or preventing arthritic disorders, including osteoarthritis, rheumatoid arthritis and other rheumatoid disease.
The “effective amounts” represent a result effective variable that would require only ordinary and routine experimentation to determine utilizing the skills of an ordinary clinician at the time of filing, particularly in view of WO’672 at 12 teaching that the dosing depends upon the “individual patient and may be determined by the medical practitioner based on individual circumstances”.
For example, determining effective amounts of B(3)-C, B(7)-C, A10E, E12E, or compound 7, would require only ordinary and routine experimentation to determine no observed adverse effect levels “NOAELs” through preclinical experimentation, followed by safety assessment then dose escalation in clinical trials. Friedman 2015 exemplifies such a process in its clinical review of rosmarinic acid, a natural compound that shows the ability to inhibit acetylcholinesterase activity (Friedman 2015 at 55, right column). Rosmarinic acid was studied in models of rheumatoid arthritis (see Friedman 2015 at 57, Table 1), and was assessed for safety and dosing by determining toxicity in animal models, assessing a NOAEL, which was then followed by human trials (Friedman 2015 at 56, right column). After safety was established in both animals and humans, the clinicians determined an “optimal dose” based upon the therapeutic effect sought. Id. at 56-57.
As another example, see CN’051, at 6-15, wherein Huperzine A was tested in various models of human disease, such as rats with osteoarthritis (CN’051 at 11, Table 5). Analogs of Huperzine A were tested at various doses in other models of inflammation (CN’051 at 9, Table 1). These results allowed the inventors of CN’051 to conclude that its compounds were effective for treating at least osteoarthritis (CN’051 at 2, claim 2), and that such compounds could be prepared in pharmaceutical compositions comprising therapeutically effective doses (CN’051 at 2, claim 5). The inventors of CN’051 exemplified administration to a human in example 17, CN’051 at 15.
Accordingly, the literature establishes for compounds of the same class with similar indications, that determining effective amounts of acetylcholinesterase inhibitors for treating patients with arthritis, including osteoarthritis, requires only ordinary and routine experimentation of optimization safety and efficacy in order to arrive at a “therapeutically effective amount”.
Therefore, claims 17-36 were obvious at the time of filing.
Prior art Cited but not Applied
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
WO’12318 teaches the use of use of B3C for treating Parkinson’s disease.
Conclusion
No claims are allowed.
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/C.E.R./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Snorrason, Ernir and Murray, James, Robert, “USE OF CHOLINESTERASE INHIBITOR FOR TREATING DISEASES ASSOCIATED WITH PROTEOLYTIC ENZYME ACTIVITY”, International Publication No. WO 9908672 A1, published 1999-02-25, hereinafter “WO’672”. This document was cited IDS received on 10/31/2024, as FOR cite 1.
2 Li, W. M., et al. "East meets West in the search for Alzheimer's therapeutics-novel dimeric inhibitors from tacrine and huperzine A." Current Alzheimer Research, vol. 4, no. 4 (2007): 386-396, hereinafter “Li 2007”.
3 Carlier, Paul R., et al. "Evaluation of short-tether bis-THA AChE inhibitors. A further test of the dual binding site hypothesis." Bioorganic & medicinal chemistry, vol. 7, no. 2 (1999): 351-357, hereinafter “Carlier 1999 B3C”.
4 Friedman, Tal. "The effect of rosmarinic acid on immunological and neurological systems: a basic science and clinical review." Journal of Restorative Medicine, vol. 4, no. 1 (2015): 50-59, hereinafter “Friedman 2015”.
5 Hua-Ming Chen and Xin Ma, “Huperzine And Its Analogs For Use As Medicine For Treating Inflammatory Diseases”, Chinese Patent Application Publication No. CN 109200051 A, published 2019-01-15, hereinafter “CN’051”. Attached hereto is also a Google machine translation of this application publication, and page numbers will refer to the machine translation. This document was cited in the IDS received on 10/31/2024, as FOR cite 2.
6 The examiner notes that the B(3)-C and B(7)-C compounds are also known as bis(3)-cognitin and bis(7)-cognitin, and that different abbreviations are used by different authors. B(3)-C is often designated B3C.
7 Hu, Shengquan, et al. "Substantial neuroprotective and neurite outgrowth-promoting activities by bis (propyl)-cognitin via the activation of alpha7-nAChR, a promising anti-Alzheimer’s dimer." ACS Chemical Neuroscience, vol. 6, no. 9 (2015): 1536-1545, hereinafter “Hu 2015”.
8 Hu, Shengquan, et al. "Bis (propyl)-cognitin protects against glutamate-induced neuro-excitotoxicity via concurrent regulation of NO, MAPK/ERK and PI3-K/Akt/GSK3β pathways." Neurochemistry international, vol. 62, no. 4 (2013): 468-477, hereinafter “Hu 2013”.
9 Schubert, Jan, et al. "Expression of the non-neuronal cholinergic system in human knee synovial tissue from patients with rheumatoid arthritis and osteoarthritis." Life sciences, vol. 91, no. 21-22 (2012): 1048-1052, hereinafter “Schubert 2012”.
10 Lv, Jiaqi, et al. "The role of the cholinergic anti‐inflammatory pathway in autoimmune rheumatic diseases." Scandinavian Journal of Immunology, vol. 94, no. 4 (July 2021): article e13092, pp. 1-12, hereinafter “Lv 2021”.
11 Zhang, Dawei, and Yue Zhou. "The protective effects of Donepezil (DP) against cartilage matrix destruction induced by TNF-α." Biochemical and Biophysical Research Communications, vol. 454, no. 1 (2014): 115-118, hereinafter “Zhang 2014”.
12 Kandil, Lamia Said, Amira Sayed Hanafy, and Sherien A. Abdelhady. "Galantamine transdermal patch shows higher tolerability over oral galantamine in rheumatoid arthritis rat model." Drug Development and Industrial Pharmacy 46.6 (2020): 996-1004, hereinafter “Kandil 2020”.
13 The Gowayed papers refer to:
Gowayed, Mennatallah A., et al. "Effect of galantamine on adjuvant-induced arthritis in rats." European journal of pharmacology, vol. 764 (2015): 547-553, hereinafter “Gowayed 2015”
Gowayed, Mennatallah A., et al. "The role of α7nAChR in controlling the anti-inflammatory/anti-arthritic action of galantamine." Biochemical Pharmacology, vol. 170 (2019): article 113665, pp. 1-11, hereinafter “Gowayed 2019”.
Gowayed, Mennatallah A., et al. "Galantamine in rheumatoid arthritis: a cross talk of parasympathetic and sympathetic system regulates synovium-derived microRNAs and related pathogenic pathways." European Journal of Pharmacology, vol. 883 (2020): article 173315, pp. 1-10, hereinafter “Gowayed 2020”.
14 Both B(3)-C and B(7)-C are encompassed by claims 17-18, 20-23 and 27-28, 30-33.
15 A10E is encompassed by claims 17-18, 20-22, 24 and 27-28, 30-32, 34.
16 E12E is encompassed by claims 17-18, 20-22, 25 and 27-28, 30-32, 35.
17 Compound 7 is encompassed by claims 17-18, 20-22, 26 and 27-28, 30-32, 39.
18 Mao Zixu and Li Wenming, “USES OF BIS(3)-COGNITIN AND RELATED COMPOUNDS”, International Publication No. WO 2013044123 A1, published 2013-03-28, hereinafter “WO’123”.
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