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 .
Application Status
2. Applicant's amendment and response, submitted on May 8, 2026, has been reviewed by the examiner and entered of record in the file.
3. Claim 10 is amended.
4. Claims 20-25, previously withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, have been rejoined for examination on the merits.
5. Claims 10, 17 and 20-25 are under examination and are the subject of this office action.
Information Disclosure Statement
6. Applicant’s information disclosure statement (IDS) submitted on May 8, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner, please refer to the signed copy of Applicant’s PTO-1449 form, attached herewith.
Previous Claim Rejections - 35 USC § 103
7. Claim 10 was previously rejected under 35 U.S.C. 103 as being unpatentable over STN Registry No. 1042898-85-0, (entered STN August 22, 2008).
8. In view of Applicant’s amendment to delete the compound species MAGLZ-II-06 from the claim, the previous obviousness rejection is withdrawn.
9. Claim 10 was previously rejected under 35 U.S.C. 103 as being unpatentable over STN Registry No. 1684443-71-7, or STN Registry No. 1684445-74-6, or 1684445-91-7, (each entered STN August 15, 2015).
10. In view of Applicant’s amendment to delete the compound species MAGLZ-II-18(a) from the claim, the previous obviousness rejection is withdrawn.
Election/Restrictions
11. Claims 10 and 17 are directed to an allowable product. Pursuant to the procedures set forth in MPEP § 821.04(B), claims 20-25, directed to the process of using an allowable product, previously withdrawn from consideration as a result of a restriction requirement, are hereby rejoined and fully examined for patentability under 37 CFR 1.104.
Because all claims previously withdrawn from consideration under 37 CFR 1.142 have been rejoined, the restriction requirement as set forth in the Office action mailed on November 18, 2024 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claim Rejections - 35 USC § 112(a)
12. 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.
13. Claims 20-25 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 a method of inhibiting MAGL in vitro comprising administering a compound of claim 10 (see Example 36) and for a method of treating depression (Examples 37-39), pain (Examples 40-42), irritable bowel syndrome (Example 43), migraine (Example 44), and ulcerative colitis (Example 45), not enabled for a method of “contacting the MAGL” in vivo or of treating any MAGL-mediated disease or condition in a mammal, as presently recited. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
14. The standard for determining whether the Specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? As recognized by the court in In re Wands, 858 F.2d 731 (Fed. Cir. 1988), that is still the standard to be applied, determined by consideration of the Wands factors (MPEP 2164.01(A)); namely, nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered, with the most relevant factors discussed below.
15. Nature of the Invention: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.”
16. In the instant case, claim 20 is drawn to a method for inhibiting MAGL, comprising contacting the MAGL with the compound or a pharmaceutically acceptable salt thereof of claim 10. Claim 21 is drawn to a method for treating a MAGL-mediated disease or condition in a mammal, comprising administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof of claim 10 to the mammal. Claim 22 is drawn to claim 21, and limits wherein the disease or condition is selected from: metabolic disorders, nephrosis, emesis or vomiting or nausea, eating disorders, neuropathy, schizophrenia, depressive disorders, bipolar disorders, fremitus, dyskinesia, abstinence syndromes, traumatic brain injury, non-traumatic brain injury, spinal cord injury, epileptic seizure, conditions associated with abnormal cell growth or proliferation, inflammatory conditions, immune system conditions, irritable bowel syndromes, ulcer colonitis, acute stress disorders, substance-inducing anxiety, obsessive-compulsive disorders, anxiety disorders; attention deficiency disorders, attention deficit hyperactivity disorders, pains, migraine, demyelinating diseases, and cognitive impairments. Claim 23 is drawn to claim 22, and limits wherein the conditions associated with abnormal cell growth or proliferation is benign tumors or cancers. Claim 24 is drawn to a method for treating a MAGL-mediated disease or condition in a mammal, comprising administering a therapeutically effective amount of the compound MAGLZ-11-18 to the mammal. Claim 25 is drawn to claim 24, and limits wherein the disease or condition is selected from: metabolic disorders, nephrosis, emesis or vomiting or nausea, eating disorders, neuropathy, schizophrenia, depressive disorders, bipolar disorders, fremitus, dyskinesia, abstinence syndromes, traumatic brain injury, non-traumatic brain injury, spinal cord injury, epileptic seizure, conditions associated with abnormal cell growth or proliferation, inflammatory conditions, immune system conditions, irritable bowel syndromes, ulcer colonitis, acute stress disorders, substance-inducing anxiety, obsessive-compulsive disorders, anxiety disorders; attention deficiency disorders, attention deficit hyperactivity disorders, pains, migraine, demyelinating diseases, and cognitive impairments.
17. The State of the Prior Art and the Level of Predictability in the Art:: As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed.”
As stated above, the claims are drawn to inhibiting a monoacylglycerol lipase inhibitor (MAGL), comprising contacting the MAGL with a compound of claim 10, or to the treatment of a MAGL-mediated disease or condition in a mammal, comprising administering a compound of claim 10 to the mammal.
18. The state of the art regarding MAGL-mediated diseases encompassed by the claims is that they embrace:
metabolic disorders (e.g., obesity), nephrosis (e.g., acute inflammatory renal injury and diabetic nephropathy), emesis or vomiting (e.g., chemotherapy-induced emesis), nausea (e.g., refractory nausea or chemotherapy-induced nausea), eating disorders (e.g., anorexia or bulimia), neuropathy (e.g., diabetic neuropathy, pellagra neuropathy, alcoholic neuropathy, beriberi neuropathy), neurodegenerative conditions [multiple sclerosis (MS), Parkinson's disease (PD), Huntington's disease, dementia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), epilepsy, frontotemporal dementia, sleep
disorders, Creutzfeldt-Jakob Disease (CJD) or prion disease], schizophrenia,
depressive disorders, bipolar disorders, fremitus, dyskinesia, dystonia, spasticity,
touretti's syndrome, abstinence syndromes [alcohol abstinence syndrome,
antidepressant withdrawal syndrome, antipsychotic withdrawal syndrome,
benzodiazepine withdrawal syndrome, Cannabis sativa abstinence syndrome, neonatal
abstinence syndrome, nicotine abstinence syndrome, or opiates abstinence syndrome],
traumatic brain injury, non-traumatic brain injury, spinal cord injury, epileptic seizure,
conditions associated with abnormal cell growth or proliferation [e.g., benign tumors
or cancers, such as, benign skin tumors, brain tumors, papilloma, prostate tumors,
brain tumors (glioblastoma, medullo-epithelioma, medulloblastoma, neuroblastoma,
astrocytoma, astroblastoma, ependymoma, oligodendroglioma, choroid plexus tumor,
neuroepithelioma, epiphyseal tumor, ependymoblastoma, malignant meningioma,
sarcosis, mclanoma and schwannoma), melanoma, metastatic tumor, renal cancer,
bladder cancer, cerebral cancer, glioblastoma (GBM), gastrointestinal cancer,
leukemia or blood cancer], inflammatory conditions [for example, appendicitis,
bursitis, colitis, irritable bowel syndrome, ulcerative colitis, urocystitis, dermatitis,
phlebitis, rhinitis, tendinitis, amygdalitis, vasculitis, acne vulgaris, chronic prostatitis,
glomerulonephritis, hypersensitivity, IBS, pelvic inflammatory diseases, sarcoidosis,
HIV encephalitis, rabies, brain abscess, neuroinflammation, central nervous system
(CNS) inflammation], immune system conditions (e.g., transplant rejection or celiac
discase), post-traumatic stress disorder (PTSD), acute stress disorder, panic disorder,
substance-induced anxiety, obsessive-compulsive disorder (OCD), agoraphobia,
specific phobia, social phobia, anxiety disorder, attention deficit disorder (ADD);
attention deficit hyperactivity disorder (ADHD); pains [e.g., acute pain, chronic pain,
inflammatory pain, visceralgia, post-surgical pain, migraine, low back pain, arthralgia,
stomachache, stethalgia, post-mastectomy pain syndrome, menstrual pain,
endometriosis pain, physical trauma-induced pain, headache, sinus headache, tension
headache, arachnoiditis, herpes virus pain, diabetic pain, and pain induced by a
condition selected from the following: osteoarthritis, rheumatoid arthritis, spondylitis,
gout, labor pain, musculoskeletal diseases, dermatosis, toothache, heartburn, burn,
sunburn, snake bite, venomous snake bite, spider bite, insect bites, neurogenic bladder,
interstitial cystitis, urinary tract infection (UTI), rhinitis, contact dermatitis/ hypersensitivity, itching, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome (IBS), cholecystitis and pancreatitis; neuropathic pains (e.g., nervous
lumbago, complex regional pain syndrome, pillar prosopalgia, causalgia, toxic
neuropathy, reflex sympathetic dystrophy, diabetic neuropathy, chronic
chemotherapeutant-induced neuropathy, or ischialgia)]; demyelinating diseases [e.g.,
multiple sclerosis (MS), Devic's disease, CNS neuropathy, central pontine myelinolysis, syphlitic myelopathy, leukoencephalopathy, leukodystrophy, Guillain-Barre syndrome, chronic inflammatory demyelinated polyneuropathy, anti-myelin-associated glycoprotein peripheral neuropathy, Charcot-Marie-Tooth Discase, peripheral neuropathy, mycleterosis, optic neuropathy, progressive inflammatory neuropathy, optic neuritis, and transverse myclitis] as well as cognitive impairments [e.g., Down's syndrome-associated cognitive impairment, Alzheimer's disease-associated cognitive impairment, PD-associated cognitive impairment, mild cognitive impairment (MCI), dementia, post-chemotherapy cognitive impairment (PCCI) and postoperative cognitive dysfunction (POCD)] (see the Specification, pages 10-12).
Thus, the recited MAGL-related diseases embrace an extremely broad spectrum of morbidity and mortality that are difficult to diagnose, let alone treat.
19. Mulvihill et al. teach that MAGL is an effective therapeutic target in the treatment of pain and inflammation and certain other inflammatory diseases including colitis, as well as demonstrating potential in certain neurodegenerative diseases such as Alzheimer’s disease, as well as anxiety, certain cancers including breast cancer, ovarian cancer, melanoma, and prostate cancer, as well as having anti-emetic and anti-nausea effects, and potential for treating addiction (pages 3-6). Mulvihill et al. go on to teach the potential unpredictability and liabilities of MAGL inhibitors: “…studies have also shown that chronic MAGL ablation produces functional antagonism of the endocannabinoid system and mild physical dependence, and impaired endocannabinoid dependent synaptic plasticity (Schlosburg et al., 2010). This is in contrast to fatty acid amide hydrolase (FAAH) inhibitors that block the hydrolysis of the other endocannabinoid anandamide, to produce sustained CB1-dependent analgesia without receptor desensitization. These results are of potential concern since CB1 receptor antagonists, such as rimonabant were withdrawn from clinical use towards treating obesity, due to increased anxiety, depression, and suicidal tendencies (Moreira et al., 2009),” (page 7, second paragraph). that this unpredictability impacts less selective JAK inhibitors: “Highly specific inhibitors can achieve more predictable responses and have less undesired side effects by having reduced off targets, whereas a wider inhibitory range can increase clinical efficacy (but possibly also side effects) by inhibiting several targets” (page 2057, right column, under “Discussion”).
20. This unpredictability is certainly true in the case of treating the vast scope of MAGL-related diseases embraced by the claims, which are complex and varied in etiology as well as severity of pathology depending on the system(s) affected in the body, muscles, skin, blood vessels, digestive system, endocrine system, and the nervous system, including metabolic disorders, nephrosis eating disorders neuropathy, neurodegenerative conditions, schizophrenia, depressive disorders, bipolar disorders, neurological conditions, traumatic brain injury, spinal cord injury, epileptic seizure, inflammatory conditions, and conditions associated with abnormal cell growth or proliferation including all types and kinds of cancer, none of which are enabled by the disclosure.
21. There is no question Applicant’s instant compounds may play a role for preparing a medication in future methods of treating certain of the aforementioned types of autoimmune or skin inflammatory diseases. What is disputed is the claim that the recited method could be employed by one skilled in the art at the effective filing date of the claimed invention and used as treatment for any/ all types and kinds of MAGL- related diseases embraced by the claims without undue experimentation. There is simply no evidence to be found in the literature suggesting that Applicant’s compounds are capable of being used in the manner recited. In essence, there is no absolute predictability in pharmacology, even with compounds whose properties have been determined, despite the extraordinarily high skill possessed by the ordinary artisan.
22. Hence, in the absence of a showing of correlation between all types and kinds of MAGL- related diseases embraced by the claims, as capable of being treated by any of the MAGL-inhibitor compounds recited in claim 10, one of skill in the art is unable to fully predict possible results from the administration of the compound(s) of the instant claims for treating the scope of MAGL- related diseases encompassed by the claims.
23. As such, one of skill in the art would be unable to fully predict the therapeutic effects of administering any of the recited MAGL inhibitors of claim 10 for the treatment of the recited MAGL- related diseases, as embraced by the instant claims.
24. Relative Skill of those in the Art: The level of skill in the art of one tasked with treating any MAGL-related diseases in a subject, i.e., physicians represent one of ordinary skill in the art.
25. The Amount of Direction Provided by the Inventor / Existence of Working Examples: The amount of direction provided by the Applicant is considered to be determined by the Specification and the working examples. In the instant case, Applicant provides no working examples demonstrating the in vivo effect(s) of inhibiting MAGL comprising contacting MAGL with a compound of claim 10. Applicant provides one example of inhibiting MAGL in vitro comprising administering a compound of claim 10 (see Example 36). The only in vivo guidance provided at all is the therapeutic effects of the compounds of claim 10 in murine models of treating depression (Examples 37-39), pain (Examples 40-42), irritable bowel syndrome (Example 43), migraine (Example 44), and ulcerative colitis (Example 45). As such, the Specification does not support the broad claim of treatment of any of the multitude of types of MAGL-related diseases embraced by the claims.
26. Scope or Breadth of the Claims: As stated in MPEP 2164.01(c), “[w]hen a compound or composition claim is limited by a particular use, enablement of that claim should be evaluated based on that limitation.” Thus, as stated in MPEP 2164.08, “[t]he focus of the examination inquiry is whether everything within the scope of the claim is enabled” (emphasis added). The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation’.” In re Wright, 999 F.2d 1557 (Fed. Cir. 1993) (emphasis added).
27. At the same time, however, it is also recognized that not everything necessary to practice the invention need be disclosed. Nor is it necessary that an Applicant test all the embodiments of his invention. In re Angstadt, 537 F.2d 498 (CCPA 1976) (emphasis added). In fact, as stated by the court in In re Buchner, 929 F.2d 660 (Fed. Cir. 1991), a patent need not teach, and preferably omits, what is well known in the art.
28. Amount of Experimentation Necessary: In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the invention as claimed. As discussed above, the claims are drawn to the use of a compound of claim 10 for inhibiting MAGL (claim 20) or for treating any MAGL-related disease (claims 21 and 24) or the broad scope of unrelated MAGL-related diseases or conditions embraced by claims 22, 23 and 25. Since identifying any MAGL- related disease that is capable of being treated by administering any of the compounds of claim 10 is extremely complex, the nature of the instant invention considered to be one of extreme complexity. In the instant case, this complexity is exacerbated by the challenges of treating any/ all types of MAGL-related diseases embraced by the claims. Although the relative skill of those in the art to which the invention pertains is high, the state of the art and unpredictability within the art is such that even the most talented artisan could not reasonably predict what disease encompassed by the claims would be treatable based on the limited disclosure which fails to provide any working examples.
29. To overcome this rejection, Applicant should narrow the scope of the claims such that they bear a reasonable correlation with the disclosure.
Conclusion
30. Claims 10, 17 and 20-25 are present in the application. Claims 20-25 are rejected. Claims 10 and 17 currently appear allowable over the prior art of record.
31. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
32. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANET L COPPINS whose telephone number is (571)272-0680. The examiner can normally be reached Monday-Friday 8:30AM-5PM EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JANET L COPPINS/Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628
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