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
Mailing Receipt and Priority
The filing receipt mailed 08/23/2023 states that the instant application is a 371 of PCT/US2021/020308, filed 03/01/2021, which claims benefit of application 62/982,717, filed 02/27/2020.
The claims find support in the provisional application. Therefore the effective filing date is 02/27/2020.
Response to amendments
The amendments made to the claims 09/11/2025 have been entered.
Information Disclosure Statement
The information disclosure statements submitted on 09/13/2022, 01/31/2024, 04/19/2024, 09/24/2024, 05/14/2025 have been considered.
Response to election
The election made in the remarks submitted 09/11/2025 is acknowledged. Applicant has elected the following compound for search and examination.
Elected compound
PNG
media_image1.png
140
288
media_image1.png
Greyscale
Applicant as also elected the following species without traverse:
-Post-partum depression (disease/condition).
At examiner’s discretion search and examination has been broaden to include all compounds represented by the formula I (claim 1) shown below:
Formula I
PNG
media_image2.png
138
272
media_image2.png
Greyscale
The examiner has also broaden search and examination to all disorders within claims 50-53.
Specification
The use of the term Zulresso™, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Rejections
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.
Scope of Enablement
Claims 49-54 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 treatment of epilepsy, status epilepticus, postpartum depression, does not reasonably provide enablement for the treatment CDKL5 deficiency disorder, major depressive disorder, post-traumatic stress disorder, fragile x syndrome, Parkinson’s disease, treatment resistant depression, other conditions named in claim 50 but not stated above as enabled, or all other conditions related to GABAA receptor function. Additionally, the claims do not provide enablement for the prevention of epilepsy, status epilepticus, postpartum depression.
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.
The following Wands factors have been considered: (A) The breadth of the claims, (B) The nature of the invention, (C) The state of the prior art, (D) The level of one of ordinary skill, (E) The level of predictability in the art, (F) The amount of direction provided by the inventor, (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Breadth of the claims
Claim 49 is drawn to a method of treating diseases or conditions related to GABAA receptor function.
Claim 50 specifies that the condition is a number of disorders ranging from sleep and mood disorders to substance abuse, tinnitus, withdrawal syndrome, movement disorder, autism, and schizophrenia.
Claim 51 is drawn more narrowly to dementia, epilepsy, and Parkinson’s disease. Claim 52 is drawn more narrowly to CDKL5 deficiency disorder, major depressive disorder (MDD), postpartum depression (PPD), essential tremor, post-traumatic stress disorder, status epilepticus, fragile x syndrome, Parkinson’s disease, or treatment resistant depression. Claim 53 is drawn to MDD, PPD, and epilepsy.
“Treatment” is defined in para. [000161] of the specification which states “The term ‘treatment’ is used synonymously with ‘therapy’.” The instant specification in para. [000159] states “The term ‘therapy’ also encompasses prophylaxis unless there are specific indications to the contrary.” It is presumed “prevention” of the claimed disease would require a method of identifying those individuals who will develop the claimed diseases before they exhibit symptoms. Preventing diseases, therefore, requires identifying those patients who will acquire the disease before the conditions occur This would require extensive and potentially opened ended clinical research on healthy subjects.
Nature of the Invention
The instant claims are drawn to compounds and methods comprised of administering said compounds which are prodrugs. The instant compounds are prodrugs of compounds allopregnanolone (brexanolone) and ganaxolone (structures below).
Allopregnanolone
PNG
media_image3.png
204
272
media_image3.png
Greyscale
Ganaxolone
PNG
media_image4.png
208
266
media_image4.png
Greyscale
Considering that the instant compounds are prodrugs, one of ordinary skill in the art would understand that the methods of treating would include any method of treating a condition comprising administering either allopregnanolone (herein after brexanolone) or ganaxolone. That is, whichever conditions or diseases that are treated with the allopregnanolone and ganaxolone above would also be enabling for the instant compounds.
State of the Art
The following references support the use of either ganaxolone or brexanolone.
Bharadwaj (International Journal of Basic and Clinical Pharmacology, 2019, Vol. 8, Iss. 5) on p. 1123 teaches the therapeutic use of Ganaxolone and Brexanolone in Table 1, shown below.
Bharadwaj, Table 1
PNG
media_image5.png
250
370
media_image5.png
Greyscale
Zolkowska (Epilepsia, vol. 159, Iss. S2, 2018, abstract only) supports the use of ganaxolone as treatment for epilepticus where it states “Allopregnanolone and ganaxolone terminated [status epilepticus]…”.
However, Rasmusson (Psychopharmacology, 2017, 234:2245-2257) on p. 2255, right col., states “In summary, this first phase 2 clinical trial of ganaxolone in PTSD showed that ganaxolone, as dosed, was safe but no more efficacious than placebo in reducing PTSD symptoms.”
A search did not result in art that could indicate any connection between specifically Ganaxolone and/or Brexanolone with treatment of other GABAA related conditions.
Regarding “prophylaxis”, the art does not discuss methods of determining whether a patient will or will not develop the claimed conditions prior to the fact.
Amount of direction
The instant disclosure does not provide any working examples or direction that would indicate that the instant compounds or even Brexanolone and/or Ganaxolone have shown efficacy in treating GABAA related conditions excluding those which have been stated have support.
There are no working examples of a preventive or “prophylaxis” procedure in the specification.
Level of unpredictability
One of ordinary skill in the art would need first test the whether the instant compounds or Brexanolone and/or Ganaxolone show efficacy against other GABAA related conditions. The art has not publicly indicated any efficacy. The art also does not discuss efficacy in preventing GABAA related conditions. Considering this, there is a significant level of uncertainty and also an undue burden should one of ordinary skill attempt to use the instant compounds in methods to treat GABAA related conditions as currently claimed.
Written Description
Claims 49-50 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 49 states “A method of treating a disease or condition related to GABAA receptor function…”.
The term “disease or condition related to GABAA receptor function” is not explicitly defined, as discussed in the 112(b) rejection below.
The instant specification beginning in para. [00156] teaches exemplary diseases or conditions related to GABAA function. However, the specification does not explicitly discuss which diseases or conditions are related to GABAA receptor function and does not disclose how one of ordinary skill in the art would be able to determine which conditions and/or diseases are related to GABAA receptor function. Therefore, the term “disease or condition related to GABAA receptor function” is broad and includes diseases and/or conditions that have not been currently shown to be related to GABAA receptor function.
Therefore, the instant specification does not fully support methods of treating diseases or conditions related to GABAA receptor function.
Claim Rejections - 35 USC § 112(b)
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 1-5, 7-9, 11-46 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.
Claim 1 states “wherein said alkyl, alkenyl, alkynyl….”. Claim 1 uses the term “alkyl” in the definition of both substituents L, W, and Y. It is unclear whether the “alkyl” of the wherein clause refers to specifically the “alkyl” of “Y” or whether it also refers to the alkyl of “L” or “W”.
As claims 2-5, 7-9, and 11-46 are dependent on claim 1, they are also rejected.
Claims 1-5, 7-9, 11-12, 17-46 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.
Claim 1 states “L is selected from the group consisting of null, alkyl, -O-, and -N(R2)-; W is selected from the group consisting of null, alkyl, and -O-;”.
The specification does not define “null” and there is no universally accepted definition of “null” within the chemical arts. The broadest reasonable interpretation would include situations where L is not existent or is replaced by a bond. However, this is still not clear because the claim and the specification does not specify whether the individual substituent (L or W) along with subsequent substituents is completely absent or if the substituent is simply replaced by a bond. Within this ambiguity are embodiments where the substituent is simply absent and is replaced with subsequent substituents. That is, should L be absent (null), W is still connected to the core moiety claimed. For the purpose of examination, the third interpretation is being used.
Claim 30 is dependent on either claim 28 or claim 29. Claim 30 recites the limitation "wherein R1b is hydrogen" in l. 2 of said claim. Claims 28 and 29 claim embodiments Ic-1, Ic-2, Id-1, and Id-2, shown below.
Claim 28 compounds
PNG
media_image6.png
202
300
media_image6.png
Greyscale
Claim 29 compounds
PNG
media_image7.png
218
304
media_image7.png
Greyscale
There is insufficient antecedent basis for the limitation “wherein R1b is hydrogen”.
Claims 49-50 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.
Claim 49 states “a disease or condition related to GABAA receptor…”
The instant specification beginning in para. [00156] teaches exemplary diseases or conditions related to GABAA function. However, the specification uses open-ended language, include or for example. The term “related” embrace an increase and decrease in GABAA receptor activity. A person skilled in the art would not be able to determine which conditions and/or diseases are embraced by said phrase since there is no standard list of diseases or conditions related to GABAA receptor function.
Considering this, one of ordinary skill would not know the metes and bounds of the claims via the claims themselves or the specification.
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) 1, 4, 5, 17,18, and 24 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Stein (WO2010/088409, of the record).
Stein on p. 56 discloses compound P1-133 and P1-135, below.
Stein Compounds
PNG
media_image8.png
164
634
media_image8.png
Greyscale
The compounds above embrace embodiments of the compound of formula I (claim 1) where L is null, W is alkyl, and Y is N, and R5 and R6 are H.
Claim(s) 1, 4, 5, 17 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by PubChem (PubChem substance record, 3beta-Acetoxy-5alpha-pregnan-20-one, 2018, of the record).
The PubChem document discloses a compound of the following structure.
PubChem compound
PNG
media_image9.png
154
240
media_image9.png
Greyscale
The compound embraces embodiments of the compound of general formula I of claim 1 where L is null, W is null, and Y is alkyl.
Claim(s) 1, 4, 5, 7, 12, 13, 17, 28, 30, 34, 35, and 36 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Bonner (WO2020/028787, published 02/06/2020).
Bonner on p. 177 discloses compound 2.2 and on p. 179. Compound 3.2 (shown below).
Bonner Compounds
PNG
media_image10.png
122
216
media_image10.png
Greyscale
PNG
media_image11.png
126
220
media_image11.png
Greyscale
Compound 2.2 embraces embodiments wherein L is -O-, W is null or alkyl, and Y is alkyl substituted with halogen. Compound 3.2 embraces embodiments where L is null, W is null, and Y is alkyl substituted with a halogen.
Claim(s) 1, 4, 5, 17, 18, 19, is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Marx (US2018/0340005).
Marx claims the following compound in claim 14.
Marx compound, claim 14
PNG
media_image12.png
158
276
media_image12.png
Greyscale
The compound above embraces embodiments of the instant claims wherein L is null, W is null, and Y is selected from alkyl wherein said alkyl is optionally substituted with saturated cycloalkyl.
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) 1, 2, 3, 4, 5, 17, 18 and 48 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stein (WO2010/088409, of the record).
Discussion of Stein from the 102 above is incorporated here.
Claims 2 and 3 are drawn to embodiments wherein R1a and R1b are both hydrogen (claim 2), or methyl (claim 3), see below.
Instant compound
PNG
media_image13.png
160
448
media_image13.png
Greyscale
Stein compounds
PNG
media_image8.png
164
634
media_image8.png
Greyscale
Stein does not disclose compounds wherein both R1a and R1b are either hydrogen or methyl. However, as discussed above, Stein teaches compounds wherein either R1a or R1b are methyl or hydrogen (claim 4). The difference essentially amounts to the substituents being homologs of each other (hydrogen for ethyl and vice versa) Regarding homologs, the MPEP section 2144.09 states “Compounds which are… position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
Therefore, claims 2 and 3 would be obvious in view of the compound of Stein as one of ordinary skill in the art would recognize the different compounds as homologs of each other.
Claim 48 is drawn to a pharmaceutical composition comprising the compound of claim 1 and at least one pharmaceutically acceptable excipient.
Stein on p. 79-87 discusses pharmaceutical compositions. Stein specifically on p. 80, l. 8-16 contemplates pharmaceutical formulations comprising the compound of its invention and a pharmaceutically acceptable carrier or diluents.
Therefore, one of ordinary skill in the art would have found the instant claims prima facie obvious at the time of the effective filing date. One of ordinary skill would find motivation to formulate the compound taught by Stein into a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier as Stein teaches the compounds can be formulated into pharmaceutical compositions for treating central nervous system injury with a reasonable assumption of success.
Claim(s) 1-5, and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over PubChem (PubChem substance record, 3beta-Acetoxy-5alpha-pregnan-20-one, 2018, of the record).
Claim(s) 1-5, 7, 12-13,17, 28, 30, and 34-36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bonner (WO2020/028787, published 02/06/2020).
Claim(s) 1-5 and 17-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Marx (US2018/0340005).
Arguments regarding claims 2 and 3 from the 103 rejection over Stein above are repeated for the separate 103 rejections over PubChem, Bonner, and Marx. The difference between instant claims 2 and 3 and the reference compounds is that R1a and R1b are either both hydrogen or both methyl. See below.
Instant Compound
PNG
media_image13.png
160
448
media_image13.png
Greyscale
PubChem compound
PNG
media_image9.png
154
240
media_image9.png
Greyscale
Bonner Compounds
PNG
media_image10.png
122
216
media_image10.png
Greyscale
PNG
media_image11.png
126
220
media_image11.png
Greyscale
Marx compound
PNG
media_image12.png
158
276
media_image12.png
Greyscale
The references teach compounds where R1a is methyl and R1b is hydrogen. Comparison to the instantly claimed compound shows that the reference compounds are homologs where R1b is hydrogen.
The MPEP section 2144.09 states “Compounds which are… position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
Therefore, one of ordinary skill in the art would have found the instant claims as prima facie obvious over the reference compounds as the compounds are homologs of each other. One of ordinary skill would find motivation in that the compounds would have similar properties.
Allowable Subject Matter
Claim 47 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Claim 47 is objected to.
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LUISALBERTO GONZALEZ whose telephone number is (571)272-1154. The examiner can normally be reached M-F 8:30-5:30.
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, Jeffrey Murray can be reached at (571) 272-9023. 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.
/L.G./Examiner, Art Unit 1624
/SUSANNA MOORE/Primary Examiner, Art Unit 1624