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 .
Detailed Action
Claims 44-52 and 56-66 are currently pending.
Claim Rejections - 35 USC § 112(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 44-52 and 56-66 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 therapeutic treatment of:
Neurodegenerative disorders mediated by mAChR M1 (M1) antagonism
Demyelinating diseases
Neuropathic diseases mediated by M1 antagonism,
does NOT reasonably provide enablement for the therapeutic treatment of:
Neurodegenerative disorders NOT mediated by mAChR M1 (M1) antagonism
Neuropathic diseases NOT mediated by M1 antagonism,
or the prevention of:
Neurodegenerative disorders
Demyelinating diseases
Neuropathic diseases,
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
In In re Wands, 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have need described. They are:
1. the nature of the invention,
2. the state of the prior art,
3. the predictability or lack thereof in the art,
4. the amount of direction or guidance present,
5. the presence or absence of working examples,
6. the breadth of the claims,
7. the quantity of experimentation needed, and
8. the level of the skill in the art.
The nature of the invention (1) and breadth of the claims (6)
The nature of the invention and breadth of Claims 44-52 and 56-66 is the therapeutic and prophylactic treatment of neurodegenerative, demyelinating, and neuropathic diseases. Paragraph 72 of the specification provides that the term “treating” includes both therapeutic AND prophylactic (preventative) treatment.
The state of the prior art (2) and the predictability or lack thereof in the art (3)
Regarding therapeutic treatment of neurodegenerative diseases, Watt (The Journal of Pharmacology and Experimental Therapeutics. Volume 338, Issue 2, August 2011, Pages 622-632) teaches “The M1AChR subtype is predominantly expressed in…brain regions…implicated in learning and memory deficits associated with the pathophysiology of Alzheimer’s disease and schizophrenia” and that M1 agonist “xanomeline showed symptom reduction efficacy in patients with both Alzheimer’s disease and schizophrenia” (Page 623, Left Col.; Page 630, Left Col.). Watt further suggests a targeted M1 agonist, “LY539039 may be worthy of subsequent clinical investigation as a therapeutic agent in…Alzheimer’s disease and schizophrenia” (Title; Page 631, Right Col.). Felder (Neuropharmacology 136 (2018) 449-458) also teaches following first generation “Xanomeline, LY593093 (Fig. 1), a selective M1 agonist was developed…to enter clinical development for treatment of cognitive impairment in Alzheimer's disease and schizophrenia” (Page 450, Right Col., 2. M1 selective orthosteric…). Alzheimer’s, a neurovegetative disease, is expected to be treated with a mechanism opposite to that which is taught in the claims (M1 antagonism). One of skill in the art might expect exacerbation of symptoms related to cognitive decline in Alzheimer’s disease or schizophrenia when administering therapeutics that antagonize M1 rather than act as agonists. Therefore, treatment is not expected to occur in Alzheimer’s or diseases wherein the disease is not mediated by M1 antagonism specifically.
Regarding therapeutic treatment of neuropathic disorders, Martino (PAIN 152 (2011) 2852–2860) teaches “The role of muscarinic receptor subtype-1 (M1) in chronic pain is unclear” (Abstract). Further, “Scopolamine and pirenzepine [M1 antagonists] completely block analgesic effects of xanomeline [M1 agonists] in the rat FCA model” (Page 2858, Fig. 5). Figure 5 demonstrates that antagonists alone are also ineffective in neuropathic models as compared to agonists alone:
PNG
media_image1.png
326
795
media_image1.png
Greyscale
.
Figure 6A displays similar results in different antagonists (Page 2858). Martino suggests that agonism rather than antagonism is vital for analgesia in neuropathic pain models and the data further suggest that antagonism has either no effect or prevents the mechanism of action of neuropathic pain alleviation by M1 agonism. Therefore, it is unclear how neuropathic pain which is not specifically mediated by M1 antagonism is to be treated by the claimed methods in view of the Martino data.
Regarding the treatment of demyelinating diseases, it appears that M1 antagonism is in fact implicated in preserving and remyelinating myelin sheaths. Deshmukh (Nature. 2013 Oct 9;502(7471):327–332.) plainly states “Evidence from a cuprizone-induced model of demyelination…indicated that the observed efficacy of this drug [benztropine] results directly from an enhancement of remyelination rather than immune suppression. Pharmacological studies indicate that benztropine functions by a mechanism that involves direct antagonism of M1 and/or M3 muscarinic receptors” (Abstract). Thus, one of skill in the art would reasonably expect therapeutic treatment to result from M1 antagonism in demyelinating diseases.
Lastly, with respect to prophylactic treatment or prevention of all of the classes of claimed diseases, no artisan would expect prevention of the conditions with complex and often unknown etiology or pathogenesis unrelated to M1 antagonism. Mays (Brain Research 1648 (2016) 553–560) teaches Neurodegenerative diseases like Prion diseases are caused by infectious, sporadic, and hereditary factors and misfolded proteins (Abstract). These diseases are not shown to be linked to M1 antagonism. Even demyelinating diseases like MS, which are expected to be therapeutically treated, would not be expected to be prophylactically treated by M1 antagonism. Ghasemi (CELL JOURNAL, Vol 19, No 1, Apr-Jun (Spring) 2017) teaches “the etiology and pathogenesis of MS remains unclear…the cause of MS is multifactorial and include genetic predisposition together with environmental factors such as exposure to infectious agents, vitamin deficiencies, and smoking. These agents are able to trigger a cascade of events in the immune system which lead to neuronal cell death accompanied by nerve demyelination and neuronal dysfunction” (Abstract). There is no suggestion or teaching in the art that M1 antagonism can reverse or mitigate these factors in the onset of a disease with such an unclear pathogenesis and etiology.
The amount of direction or guidance present (4) and the presence or absence of working examples (5)
Applicant provides assay data in Example 111 beginning on Page 114. The data suggest M1-selective antagonistic activity is exhibited by the claimed genus of Formula (IA); however, no experimental nexus is provided which would link the activity to the broad therapeutic and prophylactic activity claimed in each of the examined methods.
The quantity of experimentation needed (7)
The quantity of experimentation needed is extremely difficult, novel, and undue experimentation; the ability of the methods comprising administering novel compounds to treat and prevent the scope of diseases as claimed is nearly impossible to determine and not at all enabled by the experiments disclosed in the specifications of the application. A vast array of compounds are encompassed by the scope of Formula (IA) and a myriad of complex diseases are encompassed by applicant’s scope. One of skill in the art would be unduly burdened having to select one of the many of compounds of Formula (IA) and devising experiments to determine prophylactic or therapeutic efficacy of said compounds in diseases which may or may not be well characterized in terms of their onset and pathology.
The level of the skill in the art (8)
The level of skill in the art is high. However, even one of the highest skill in the pharmaceutical arts would not, without undue experimentation, be able to treat and prevent the vast genus of diseases claimed with the innumerable embodiments of Formula (IA).
Thus, the specification fails to provide sufficient support of the broad use of the methods of the instant claims for the treatment and prevention of the claimed genera of disorders.
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.
NONPROVISIONAL:
Claims 44-52 and 56-66 are rejected on the grounds of nonstatutory double patenting as being unpatentable over Claims 1-18 of U.S. Patent No. 12054487 (hereinafter referred to as Schrader) in view of Leger (Neurotherapeutics (2016) 13:96–107).
Although the claims at issue are not identical, they are not patentably distinct from each other because both applications are directed to the same genus of Formula (IA) and embodiments thereof (e.g.,
PNG
media_image2.png
88
349
media_image2.png
Greyscale
vs.
PNG
media_image3.png
48
169
media_image3.png
Greyscale
) for use in modulating M1 receptors.
Regarding the claims directed to compositions of matter, In AbbVie Inc. v. Kennedy Institute of Rheumatology Trust, 764 F.3d 1366, 112 USPQ2d 1001 (Fed. Cir. 2014), 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). See MPEP 804 (II) (B) (1).
Schrader teaches the compounds for the treatment of neurodegenerative diseases, peripheral neuropathies, diabetic neuropathy, MS, and demyelinating diseases of the PNS (Col. 8-9).
Schrader does not claim co-administering immunomodulators.
Leger teaches IFN-β1a, an IFN-β1 molecule as claimed, is known to be used and effective in the treatment of multiple sclerosis, a demyelinating and neurodegenerative autoimmune disease, and exhibited “improvement in clinical grading” with therapeutic effects related to IVIG therapy in CIDP, a neuropathy (Page 100, IFN-β1a).
In re Kerkhoven (205 USPQ 1069, 626 F2d 846) teaches “It 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 which is to be used for the very same purpose.” See MPEP 2144.06. The compounds of Schrader and Leger are all directed toward the treatment of neurodegenerative diseases, demyelinating diseases, and neuropathy. Therefore, it is prima facie obvious to form a composition comprising the examined compounds and that of Leger, IFN-β1a, and expect that treatment would result from the combined agents that are effective treatments against said diseases alone.
Since both claim sets teach the same compounds for the same use, the examiner maintains that the aforementioned claims of the instant application are substantially overlapping in scope as discussed hereinabove and are prima facie obvious over the cited claims of Schrader.
Conclusion
No claim is allowable.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Richard G. Peckham whose telephone number is (703)756-4621. The examiner can normally be reached 8:30am - 4:30pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney Klinkel can be reached on (571) 270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/RICHARD GRANT PECKHAM/Examiner, Art Unit 1627
Prosecution Insights