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 .
Status
Claims 1, 4, 10-14, 31, and 47 are pending and under examination. Several claims were amended for increasing readability.
Election/Restrictions
Applicant elected Group I (drawn to a method of treating), premenstrual syndrome (PMS) as the neuroinflammatory condition, and amitriptyline as the agent in the reply filed on 12/9/2024.
Priority
This application is a U.S. National Phase of International Patent Application No. PCT/AU2020/050551, filed on May 29, 2020, which claims priority to Australian Provisional Patent Application 2019901883 filed on 31 May 2019. Applicant’s claim to priority is acknowledged.
Information Disclosure Statement
The Information Disclosure Statement(s) filed 3/6/2026 has/have been considered by the Examiner. The submission(s) is/are in compliance with the provisions of 37 CFR §§ 1.97 and 1.98. Enclosed with this Office Action is a return-copy of the Forms PTO-1449 with the Examiner’s signature and indication of those references that have been considered.
Claim Rejections - 35 USC § 103
Rejection maintained
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.
Claims 1, 4, 10-14, 31 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over E. Taghavi (Australian and New Zealand Journal of Psychiatry 1990; 24:276-279) in view of Gupta et al. (“Pharmacokinetic and pharmacodynamic characterization of OROSA and immediate-release amitriptyline.” Br. J. Clin. Pharmacol., 48, 71–78) and M. Sillender (WO 2014/121332 – 11/29/2021 IDS ).
Claimed invention
Claim 1 is drawn to a method of treating a female subject suffering from, or susceptible to, a neuroinflammatory condition (e.g., premenstrual syndrome – “PMS”), the method comprising intrauterine administration to the subject of an effective amount of amitriptyline as an agent that reduces activation of the innate immune system and thereby treating the subject.
Prior art
Taghavi teaches treatment of women with PMS, i.e., a neuroinflammatory condition, comprising administering amitriptyline, i.e., an agent that reduces activation of the innate immune system. See abstract; see also para. bridging columns at page 277 and see also ‘Treatment’ section on page 278.
However, Taghavi does not expressly teach intrauterine administration of amitriptyline.
But it was already known that oral administration of amitriptyline undergoes extensive first-pass metabolism and elimination that drastically lowers its bioavailability and it was known that such agents can be therapeutically administered by intrauterine delivery to enhance bioavailability. For example, Gupta teaches “amitriptyline undergoes extensive hepatic presystemic elimination, and its systemic bioavailability ranges from 33% to 62% after oral administration.” (Gupta, p. 72, first para.; see also p. 78, first column.) Sillender discovered a device and a method for delivering therapeutic substances in a controlled manner over a sustained time period, especially substances which may be inactivated by digestive enzymes or by passage through the liver upon ingestion. (Sillender, p. 1, ‘Background’.) Therapeutics that control neuralgic-related pain including amitriptyline can be administered using the intrauterine delivery system of Sillender. (Sillender, p. 13, first sentence.) The invention allows for delivery directly to an internal mucosal surface and absorbed without inactivation by the digestive enzymes of by passage through the liver. (Sillender, p. 20, lines 16-18.)
A person of ordinary skill in the art (POSA) would have found it obvious to treat PMS in a woman comprising intrauterine administration of effective amounts of amitriptyline because Taghavi teaches PMS can be treated in women by administering effective amounts of amitriptyline, which has reduced bioavailability due to first-pass metabolism in the liver after oral ingestion (Gupta); and Sillender teaches therapeutics that have reduced bioavailability due to first-pass metabolism or digestive enzymes can be delivered via intrauterine administration to deliver directly to the mucosa, bypassing issues caused by first-pass metabolism and digestive enzymes. The artisan would have administered amitriptyline via intrauterine delivery to avoid the known issue of reduced bioavailability due to first-pass metabolism and digestive enzyme activity after oral administration.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Claim 4 limits Claim 1, wherein: (i) the agent reduces activation of a pattern recognition receptor; (ii) the agent reduces activation of spinal glial cells; (iii) the agent reduces activation of spinal astrocyte cells; and/or (iv) the agent reduces activation of circulating innate immune cells. Amitriptyline reduces activation of spinal glial cells as evidenced by the specification at para. 0093 and 0314:
“…amitriptyline is effective in a mouse model at reducing spinal glial activation…”
See Specification, 0093.
Claim 10 limits Claim 1, wherein the administration of the agent to the subject comprises administering a dose of less than 100 µg/kg/day (i.e., 0.100 mg/kg/day). Taghavi teaches the initial dose of amitriptyline was between 50 to 150 mg nocte and maintenance dose was between 25 to 75 mg nocte (i.e., 0.29 to 0.88 mg/kg/day for an 85 kg woman). While Taghavi does not expressly teach 100 µg/kg/day, Taghavi’s invention provides a number of advantages including sustained mode of action without peaks or troughs over an extended period, thus allowing lower doses and preventing problems of compliance with medication. See p. 20, lines 21-24. Therefore, the POSA would have found a dose of less than 100 µg/kg/day to be obvious because Taghavi teaches lower doses of the therapeutic can be administered over a sustained period of time while bypassing inactivation after oral administration.
Claim 11 limits Claim 1, wherein the administration of the agent comprises continuous administration to the subject. Claim 13 limits Claim 1, wherein the administration of the agent comprises release of the agent from an intrauterine device. Claim 31 limits Claim 1, wherein the intrauterine administration is performed with an intrauterine device. Sillender teaches the therapeutic is administered using a catheter placed into the cervical opening to release the therapeutic agent slowly and continuously into an endocervix or other internal mucosal surfaces of a recipient. The endocervix is the mucous membrane lining the canal of the cervix uteri and/or the region of the opening of the cervix into the uterine cavity. (Sillender, p. 8, lines 5-13.) The catheter is in the uterus through the cervix at the same time or several hours or several days or longer before the delivery of a therapeutic substance is commenced. (Sillender, p. 11, lines 20-24.)
Claim 12 limits Claim 1, wherein the method further comprises administration of a sex hormone and/or an agent that modulates production and/or activity of a sex hormone. Taghavi further teaches a number of agents have been used to treat PMS, including, inter alia, estrogens, progestagens, prolactin, aldosterone, gonadotropin, and danazol. (Taghavi, p. 278, para, bridging columns.) The POSA would have found it obvious to combine administration of either one of estrogens, progestagens, prolactin, aldosterone, gonadotropin, or danazol in combination with amitriptyline because amitriptyline is known for treating PMS and the use of each one of estrogens, progestagens, prolactin, aldosterone, gonadotropin, and danazol is also known for treating PMS. The POSA would have combined any one of them with amitriptyline in order to combine their effects in the treatment of PMS.
Claim 14 limits Claim 1, wherein the subject is a human subject. Taghavi teaches the treatment of women. (Taghavi, p. 278, ‘Treatment’ section.)
Claim 47 limits claim 1, wherein the treatment improves or reduces an affective symptom and/or behavioral symptom in the subject, said symptom being selected from one or more of mood swings, tearfulness, sensitivity to rejection, irritability, anger, marked depressed mood, hopelessness, self-deprecating thoughts, anxiety, tension, difficulty concentrating and a sense of feeling overwhelmed. Although these features are mentioned in the wherein clause, they do not give further meaning and purpose to the manipulative steps of administering the therapeutic agent for the treatment of the patient. Therefore, the above phrase in the "wherein" clause is not given patentable weight because it simply expresses the intended result of the process steps positively recited. Even if these features were given patentable weight, the claim would still be rendered obvious by the teaching of Taghavi that amitriptyline controls diverse PMS symptoms including tension. See Taghavi at p. 278, 2nd col. Thus, a POSA would have found amitriptyline’s control of tension in a woman experiencing PMS to be obvious.
Response to Applicant’s arguments
Applicant argues that the Sillender delivery device is not an intrauterine device that is used for intrauterine delivery because even though it is placed in the uterus, it delivers medication to the endocervix and not the uterus. This is not persuasive because the device is inserted in the uterus through the cervical canal and drug is delivered into the endocervix which is the mucous membrane lining the canal of the cervix uteri and/or the region of the opening of the cervix into the uterine cavity. Not only is the drug intended to be released into the endocervix including at the internal opening into the uterus, it is to be released into “other internal mucosa”. See p. 8, lines 9-13. While Sillender critiques intrauterine devices which, due to their high location, causes medication to linger there, he does not disparage intrauterine delivery of drug. See Background, particularly paragraph bridging pages 1 and 2.
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 1, 4, 10-14, 31 and 47 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims of U.S. Patent No. 11,400,059 (reference claims) in view of E. Taghavi (Australian and New Zealand Journal of Psychiatry 1990; 24:276-279) in view of Gupta et al. (“Pharmacokinetic and pharmacodynamic characterization of OROSA and immediate-release amitriptyline.” Br. J. Clin. Pharmacol., 48, 71–78) and M. Sillender (WO 2014/121332 – 11/29/2021 IDS).
Claimed invention
Claim 1 is drawn to a method of treating a female subject suffering from, or susceptible to, a neuroinflammatory condition (e.g., premenstrual syndrome – “PMS”), the method comprising intrauterine administration to the subject of an effective amount of amitriptyline that reduces activation of the innate immune system and thereby treating the subject.
Prior art
The reference claims teach a method of treating pain, and/or pain related symptoms, associated with dysmenorrhea in a subject, the method comprising intrauterine administration to the subject of an effective amount of an agent that inhibits Toll-like Receptor 4 (TLR4) and that reduces activation of the innate immune system including amitriptyline, thereby treating the pain and/or the pain related symptoms in the subject.
While the reference claims teach intrauterine administration of amitriptyline to treat pain associated with dysmenorrhea, the reference claims do not expressly teach treating PMS.
However, it was already known that amitriptyline is used to treat PMS but it undergoes extensive metabolism and elimination that drastically lowers its oral bioavailability. For example, Taghavi teaches treatment of women with PMS, i.e., a neuroinflammatory condition, comprising administering amitriptyline, i.e., an agent that reduces activation of the innate immune system. See abstract; see also para. bridging columns at page 277 and see also ‘Treatment’ section on page 278.
Gupta teaches “amitriptyline undergoes extensive hepatic presystemic elimination, and its systemic bioavailability ranges from 33% to 62% after oral administration.” (Gupta, p. 72, first para.) Sillender discovered a device and a method for delivering therapeutic substances in a controlled manner over a sustained time period, especially substances which may be inactivated by digestive enzymes or by passage through the liver upon ingestion. (Sillender, p. 1, ‘Background’.) Therapeutics that control neuralgic-related pain including amitriptyline can be administered using the intrauterine delivery system of Sillender. (Sillender, p. 13, first sentence.) The invention allows for delivery directly to an internal mucosal surface and absorbed without inactivation by the digestive enzymes of by passage through the liver. (Sillender, p. 20, lines 16-18.)
A person of ordinary skill in the art (POSA) would have found it obvious to treat PMS in a woman comprising intrauterine administration of effective amounts of amitriptyline because Taghavi teaches PMS can be treated in women by administering effective amounts of amitriptyline, which has reduced bioavailability due to first-pass metabolism in the liver after oral ingestion (Gupta); and the reference claims teach amitriptyline can be delivered therapeutically via intrauterine administration while Sillender teaches therapeutics having reduced bioavailability due to first-pass metabolism or digestive enzymes can be delivered via intrauterine administration to deliver the drug directly to the mucosa, bypassing issues caused by first-pass metabolism and digestive enzymes. Therefore, the artisan would have administered amitriptyline via an intrauterine device to avoid the known issue of reduced bioavailability.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Claim 4 limits Claim 1, wherein: (i) the agent reduces activation of a pattern recognition receptor; (ii) the agent reduces activation of spinal glial cells; (iii) the agent reduces activation of spinal astrocyte cells; and/or (iv) the agent reduces activation of circulating innate immune cells. Amitriptyline meets at least one of the limitations of each one of these claims as evidenced by the specification at para. 0093 and 0314:
“…amitriptyline is effective in a mouse model at reducing spinal glial activation…”
See Specification, 0093.
Additionally, the reference claims teach the agent that inhibits Toll-like Receptor 4 (TLR4) and that reduces activation of the innate immune system is amitriptyline. See reference claim 4.
Claim 10 limits Claim 1, wherein the administration of the agent to the subject comprises administration a dose of less than 100 mg/kg/day (i.e., 0.100 mg/kg/day). The reference claims teach the method comprises administration to the subject of a dose of the agent of less than 100 mg/kg/day.
Claim 11 limits Claim 1, wherein the administration of the agent comprises long term continuous administration to the subject. Claim 13 limits Claim 1, wherein the administration of the agent comprises release of the agent from an intrauterine device. Claim 31 limits Claim 1, wherein the intrauterine administration is performed with an intrauterine device, the device comprising the agent, wherein the agent is a releasable agent that reduces activation of the innate immune system. The reference claims teach administration of the agent includes the agent being released from the device providing long-term continuous administration to the subject. See reference claims 5 and 8.
Claim 12 limits Claim 1, wherein the method further comprises administration of a sex hormone and/or an agent that modulates production and/or activity of a sex hormone. The reference claims teach the method further comprises a releasable sex hormone and/or an agent that modulates production and/or activity of a sex hormone. See reference claims 13.
Claim 14 limits Claim 1, wherein the subject is a human subject. Taghavi teaches the treatment of women. (Taghavi, p. 278, ‘Treatment’ section.)
Claim 47 limits claim 1, wherein the treatment improves or reduces an affective symptom and/or behavioral symptom in the subject, said symptom being selected from one or more of mood swings, tearfulness, sensitivity to rejection, irritability, anger, marked depressed mood, hopelessness, self-deprecating thoughts, anxiety, tension, difficulty concentrating and a sense of feeling overwhelmed. Although these features are mentioned in the wherein clause, they do not give further meaning and purpose to the manipulative steps of administering the therapeutic agent for the treatment of the patient. Therefore, the above phrase in the "wherein" clause is not given patentable weight because it simply expresses the intended result of the process steps positively recited. Even if these features were given patentable weight, the claim would still be rendered obvious by the teaching of Taghavi that amitriptyline controls diverse PMS symptoms including tension. See Taghavi at p. 278, 2nd col. Thus, a POSA would have found amitriptyline’s control of tension in a woman experiencing PMS to be obvious.
Response to Applicant’s remarks
Applicant relies on argument above about the secondary reference. But for reasons set forth above, the argument is not persuasive. Therefore, the rejection is deemed to still be proper and is, therefore, maintained.
Conclusion
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached on (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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