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
This application is a 371 of PCT/US20/20709 03/02/2020 which claims domestic benefit to provisional applications 62/937,653 11/19/2019, 62/929,694 11/01/2019 and 62/812,309 03/01/2019.
Claim Status
Applicant’s remarks filed October 17, 2025 have been entered. The Examiner respectfully notes claim 4 remains canceled. Thus, claims 1-3 and 5-16 as filed on March 11, 2025 are examined on the merits herein.
Response to Arguments
The rejection of claims 1-3 and 5-16 under 35 U.S.C. 103 is maintained as discussed below.
Applicant argues:
(A) A person of skill in the art would not have been motivated to combine this trio of references to arrive at the claimed invention of using J147 to treat or prevent post-operative cognitive dysfunction (POCD), see Applicant’s remarks, pg. 2, claim rejections – 35 U.S.C. § 103, paragraph 2.
(B) Maze does not teach or suggest the use of J147 for POCD, see Applicant’s remarks, pg. 2, claim rejections – 35 U.S.C. § 103, paragraph 2.
(C) Maze does not suggest that any generic material drawn from the broad and diverse category of materials having anti-inflammatory effect are suitable for treating POCD, see Applicant’s remarks, pg. 2, claim rejections – 35 U.S.C. § 103, paragraph 2.
(D) Schubert does not teach the use of J147 for POCD and its teachings would not motivate a person of skill in the art to substitute J147 for the TNF-α antagonists of Maze in the treatment of POCD, see Applicant’s remarks, pg. 2, claim rejections – 35 U.S.C. § 103, paragraph 2.
(E) POCD has a distinct etiology from diabetes and neurodegenerative diseases and therefore treatments for diabetes and neurodegenerative diseases are not analogous to treatments for POCD; and nothing in Maze suggest that therapeutics for diabetes or neurodegenerative diseases are or would be suitable for POCD, see Applicant’s remarks, pg. 2, claim rejections – 35 U.S.C. § 103, paragraph 2.
(F) A person of skill in the art would not have been motivated to combine Schubert with Maze and Daugherty as these references do not contain relevant teachings that would motivate the use of J147 in the POCD treatments described by Maze, see Applicant’s remarks, pg. 2, claim rejections – 35 U.S.C. § 103, paragraph 2.
(G) Daugherty teaches away from using J147 as a substitute for a TNF-α antagonist of Maze as J147 was without significant effect on tumor necrosis factor alpha (TNFα), see Applicant’s remarks, pg. 3, paragraph 1.
(H) The Examiner fails to take into account this most salient statement in Daugherty about the lack of effect of J147 on wild-type or control mice, and thus the Examiner looks to statements in Daugherty about diabetic mice even though diabetes is not analogous to POCD and there is no reason a person of skill in the art would be motivated to apply proposed diabetes therapies for treatment of POCD because the effect on TNF-α signaling reported by Daugherty is limited to diabetic mice and expressly excludes non-diabetic mice and thus a person of skill in the art would not have been motivated to combine Daugherty with Maze and Schubert, see Applicant’s remarks, pg. 3, paragraph 2.
(I) The Examiner relies upon non-analogous art in Daugherty in its application to Maze in view of the non-overlapping nature of the etiologies of POCD and diabetes. Thus, the Examiner relies upon impermissible application of hindsight in seeking to connect Schubert and Maze through Daugherty despite Daugherty’s teaching away from an expectation that J147 would serve as a TNF-α antagonist in non-diabetic mice, see Applicant’s remarks, pg. 3, paragraph 3.
With respect to Applicant’s arguments (A)-(I), the Examiner respectfully disagrees, as the Examiner respectfully notes Maze teaches preventing or reducing POCD in a patient following the inflammatory trigger, for example surgery or diabetes as discussed in the 103 rejection below, wherein said patient is administered a therapeutically effective amount of a Tumor Necrosis Factor alpha (TNFα) antagonist, and wherein Maze envisages the symptoms of POCD may include memory loss and memory impairment as discussed in greater detail in the 103 rejection below.
In addition, Schubert teaches an inventive compound of formula (I) exemplified by J147 is useful in treatment of a variety of indications; including diabetes and any disease or disorder where reducing or ameliorating memory loss is desirable, as discussed in greater detail in the 103 rejection below.
Moreover, Daugherty demonstrates J147 treatment reduced the relative concentration of TNFα as compared to the vehicle in western blot analysis of whole brain lysates of diabetic mice as discussed in greater detail in the 103 rejection below.
Daugherty teaches diabetes increased levels of tumor necrosis factor alpha (TNFa) when compared to vehicle treated control mice, but treatment of diabetic mice with J147 from the onset of diabetes caused a significant reduction in the level of this protein as discussed in the 103 rejection below.
Daugherty also teaches J147 reverses cognitive impairment in a mouse model of Alzheimer’s disease (AD), and enhances memory in both transgenic AD mice and aged wild-type mice as discussed in the 103 rejection below.
Therefore, the combination of Maze, Schubert and Daugherty teach J147 as a TNFα antagonist for preventing or reducing POCD induced or the result of surgery or diabetes as the inflammatory trigger as required in claim 1.
Thus, the combination of Maze, Schubert and Daugherty provide a rationale of including J147 into the method of Maze, as Schubert teaches J147 as a compound for treating a variety of indications which includes both diabetes and reducing or ameliorating memory loss; as Maze envisages memory loss to be a symptom of POCD treated by administering a TNFα antagonist when administering agents for reducing cognitive decline in patients following surgery or other inflammatory triggers, where Maze explicitly envisages both diabetes and surgery to be the inflammatory trigger; and as Daugherty demonstrated with treatment of J147 it reduced the relative concentration of TNFα as compared to the vehicle in western blot analysis of whole brain lysates of diabetic mice as discussed above; and wherein Daugherty already teaches J147 reverses cognitive impairment in a mouse model of Alzheimer’s disease (AD), and enhances memory in both transgenic AD mice and aged wild-type mice.
Therefore, based on the teachings of Maze, Maze envisages both surgery and diabetes as an inflammatory trigger that results in cognitive decline of a patient, and further exemplifies post-operative cognitive dysfunction (POCD) as the cognitive decline exhibited by the patient.
Moreover, Schubert teaches J147 as a compound to treat both diabetes and any disease or disorder where reducing or ameliorating memory loss is desirable; and wherein Daugherty already teaches J147 enhances memory in both transgenic AD mice and aged wild-type mice; and demonstrated reducing TNF-α protein in whole brain lysates of diabetic mice when administered J147.
Furthermore, as evidenced by Safavynia et al. (Published 17 January 2019, frontiers in Psychiatry, Vol. 9, Article 752, pp. 1-21, IDS filed 10/17/2025), Safavynia discloses chronic inflammatory states, such as diabetes, have been proposed as a potential risk factor for POCD, see pg. 2, left column, paragraph 2.
Safavynia further discloses that in aged mice, microglial activation is increased in POCD, wherein activated microglia are known to release TNFα in a variety of rodent models, see pg. 4, lefty column, paragraph 3.
Safavynia also discloses open abdominal surgery under local anesthesia caused increases in hippocampal TNFα and memory impairments, see pg. 7, left column, evidence from animal models, paragraph 1.
Finally, as demonstrated by the teachings of Maze, Schubert and Daugherty as discussed above the teachings of these references is analogous art as the method of Maze is explicitly drawn to reducing cognitive decline in patients by administering a TNF-α antagonist following surgery or other inflammatory triggers such as diabetes as taught by Maze; wherein Schubert teaches the exemplary compound of J147 in treating a wide variety of indications including diabetes or exemplary neurological indications of any disease or disorder where reducing or ameliorating memory loss is desirable; and as evidenced and taught by Daugherty, Daugherty demonstrates J147 is a TNF-α antagonist in reducing TNF-α protein in whole brain lysates of diabetic mice; and that J147 enhances memory in both transgenic AD mice and aged wild-type mice as discussed above.
Thus, Applicant’s arguments (A)-(I) have been fully considered but are not found persuasive.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3 and 5-16 remain rejected under 35 U.S.C. 103 as being unpatentable over Maze et al. (Published 17 November 2016, US 20160333088 A1, PTO-892 mailed 05/08/2024) in view of Schubert (Published 02 December 2010, Filed 14 October 2008, US 20100305181 A1, IDS filed 09/01/2021) and Daugherty et al. (Published 06 November 2017, Neuropharmacology, Vol. 129, pp. 26-35, PTO-892 mailed 04/21/2025).
Regarding claims 1-3 and 5-16, Maze teaches the present invention relates to methods, uses and agents for reducing cognitive decline in patients following surgery or other inflammatory triggers, see paragraph [0001]; where Maze defines “inflammatory trigger” to include any insult to the body that results in an inflammatory response, where if left unchecked, may lead to an overactive neuroinflammatory response and cause or worsen (if a cognitive disorder is already present) the cognitive condition of patients, wherein Maze exemplifies the inflammatory trigger includes either surgery or diabetes, see paragraph [0029].
Maze explicitly teaches the planned inflammatory trigger is surgery and the method, use or agent is thus for reducing post-operative cognitive dysfunction (POCD) in said patient, see paragraph [0012].
Maze envisages that the symptoms of POCD may include memory loss and memory impairment, see paragraph [0017].
Maze teaches preventing or reducing cognitive decline in a patient following the planned inflammatory trigger in said patient comprising administering a therapeutically effective amount of a Tumor Necrosis Factor alpha (TNFα) antagonist to said patient, see paragraph [0008]. Maze defines “TNFα antagonist” to include any compound that targets TNFα itself, see paragraph [0055].
Maze teaches systemic administration may be appropriate to patients who are undergoing multiple surgical procedures, or where the surgical procedure results in major trauma to the body, see paragraph [0036].
Maze teaches that the surgical procedure in any aspect of the invention may be colorectal, hepatobiliary, or upper-gastrointestinal surgical procedures, see paragraph [0072].
Maze teaches the patient may include a human, a mouse or a rat, but it is preferred the patient is human, see paragraph [0053]; and when the patient is a human it is envisaged that they may be often over 50 years of age, see paragraph [0054].
Maze teaches that the patient while potentially not already having been diagnosed with a cognitive disorder, may be at risk of developing one; thus Maze envisages the invention may also benefit patients who are at risk of developing a cognitive disorder (e.g. the subject displays stable cognitive function prior to surgery, required in claim 10), see paragraph [0030].
Maze also envisages that patients who may benefit from the aspects of the invention relating to POCD may have or be at risk of (e.g. the subject was not previously diagnosed with a neurodegenerative disease prior to surgery, required in claim 11) developing cognitive disorders such as and including, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and dementia, see paragraph [0052].
Maze teaches the TNFα antagonist may be administered to the patient before commencement of a surgical procedure or during a surgical procedure, see paragraph [0049]; or after completion of a surgical procedure on said patient, see paragraph [0050].
Maze teaches as an example in topical administration, the antagonist of the invention may be of the order of fractions of or multiple mg/kg body weight of the patient, and provides the example that may be 4 to 50 mg/kg, see paragraph [0043].
Maze teaches the antagonist may be administered systematically for example by intravenous administration, see paragraph [0036].
Although, Maze does not teach administering a compound of the structure of formula I, required in claims 1-3 and 5-16.
However, in the same field of endeavor of TNFα antagonists, Schubert teaches inventive compounds that have anti-inflammatory ability to impart a variety of beneficial physiological effects and such compounds are useful treatment of a variety of indications, see paragraph [0007]. Schubert teaches treating a wide variety of indications including diabetes or exemplary neurological indications of any disease or disorder where reducing or ameliorating memory loss is desirable, see paragraph [0106].
Schubert teaches an exemplary compound of formula (I) having the structure
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, see pg. 19, paragraph #19; wherein the aforementioned compound is known as J147, see paragraph [0091]. The Examiner notes that J147 meets all structural limitations required in subsection (i) of formula (II) of claim 2; and formula IV of claim 3. Schubert teaches exemplary data shows that Alzheimer’s disease (AD) mice have a deficit in memory relative to wild type animals that is corrected by the ingestion of J147, see paragraph [0022].
Schubert teaches a composition which includes a compound having the structure of Formula (I) and a pharmaceutically acceptable carrier, see paragraph [0096]; and amenable to intravenous delivery, see paragraph [0099].
Although, Schubert does not teach J147 as a TNFα antagonist. However, Daugherty teaches J147 treatment was confirmed by its capacity to decrease TNFα pathway activation and several other markers of neuroinflammation in the CNS, see pg. 26, abstract.
Daugherty teaches in Fig. 3 the impact of J147 on pro-inflammatory markers in diabetic mice, wherein western blot analysis of whole brain lysates shows the TNFα levels in Fig. 3A, and showed J147 treatment reduced the relative concentration of TNFα as compared to the vehicle in Fig. 3B, see pg. 31, Figs. 3A and 3B.
Daugherty teaches diabetes increased levels of tumor necrosis factor alpha (TNFa) when compared to vehicle treated control mice, but treatment of diabetic mice with J147 from the onset of diabetes caused a significant reduction in the level of this protein, see pg. 29, right column, section 3.3, paragraph 1 – pg. 30, left column, paragraph 1.
Daugherty also teaches J147 reverses cognitive impairment in a mouse model of Alzheimer’s disease (AD), and enhances memory in both transgenic AD mice and aged wild-type mice, see pg. 27, left column, paragraph 1.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the invention’s effective filing date to have added the intravenous delivery of a pharmaceutical composition which includes a compound of formula (I) having anti-inflammatory ability exemplified as J147 as taught by Schubert above into the method of preventing or reducing post-operative cognitive dysfunction (POCD) as taught by Maze; as Maze teaches preventing or reducing cognitive decline, for example POCD, in a patient following a planned inflammatory trigger, for example surgery or diabetes, in said patient comprising administering a therapeutically effective amount of a Tumor Necrosis Factor alpha (TNFα) antagonist to said patient as taught by Maze. In addition, Daugherty demonstrates that treatment with J147 antagonizes TNFα by reducing the relative concentration of TNFα in whole brain lysates of diabetic mice as taught by Daugherty above.
Thus, the addition of administering J147 as taught by Schubert into the method of Maze as discussed above is within the scope of the artisan as combining prior art elements according to know methods to yield predictable results. One of ordinary skill in the art would have been motivated to administer a pharmaceutical composition containing J147 as taught by Schubert; as Maze teaches preventing or reducing POCD by administering a TNFα antagonist, and wherein Daugherty demonstrates treatment with J147 reduces the levels of TNFα in whole brain lysates of diabetic mice. One of ordinary skill in the art would have had a reasonable expectation of success to make the addition described above as Maze defines a “TNFα antagonist” to include any compound that targets TNFα itself and explicitly includes both diabetes and surgery as an inflammatory trigger for reducing cognitive decline in patients; and wherein Maze exemplifies POCD as reducing cognitive decline in patients as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have added administering J147 as taught by Schubert into the method of Maze as within the scope of the artisan as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to administer J147 as taught by Schubert into the method of reducing post-operative cognitive dysfunction (POCD) as taught by Maze, as Maze teaches treating POCD induced by surgery or diabetes as the inflammatory trigger with a TNFα antagonist, and as Daugherty demonstrates J147 antagonizes the transcription of TNFα thereby reducing its relative concentration in whole brain lysates from diabetic mice as discussed above. One of ordinary skill in the art would have had a reasonable expectation of success to have made the addition as discussed above into the method as taught by Maze, as Maze defines a “TNFα antagonist” to include any compound that targets TNFα itself as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
Conclusion
No claims are allowed in this action.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARET J CREWS whose telephone number is (571)270-0962. The examiner can normally be reached Monday-Friday: 9:00am-5:30pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Renee Claytor can be reached at (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARET J CREWS/Examiner, Art Unit 1691
/SAVITHA M RAO/Primary Examiner, Art Unit 1691