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
Case Abandoned on 01/10/2024; Petition for revival received 04/12/2024; Granted 05/24/2024
Second (2nd) Non-Final Rejection
Claim Status
Claims 1, 4-14 and 16-18, were pending in the prior Office Action.
Upon amendment entry, Claims 2-5 and 12-15 are cancelled.
Claims 1, 6-11 and 16-17 are pending examination.
Priority Status
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No Foreign priority is claimed; effective filing date is acknowledged as 04/29/2022.
Information Disclosure Statement
All references have been considered in the one (1) IDS(s) filed 03/02/2026 unless marked with a strikethrough.
Examiner Responses to Arguments/Amendments
The issues raised in the prior Office Action, are addressed below:
I. Response to Interview –
Examiner sincerely thanks Applicant's representatives Arnold Newman; Antoine Karsenty; and Nikhil A. Heble, for the video interview on January 29, 2026. Due to death of the prior Council, the following amendments and arguments presented are consistent with the scientific results explained by Inventor and includes a review of the prior Office Actions.
II. Claim Amendments –
Upon amendment entry, Claim 1 was amended to the following:
“A method for treating post-operative cognitive dysfunction, comprising administering an effective amount of pirfenidone to a mammalian subject in need thereof.”
Also, upon amendment entry, Claim 6-11, and 16-17 were amended to reflect wherein the compound of pirfenidone is administered and used in a method for treating post-operative cognitive dysfunction.
III. Response to Duplicate Claim Warning -
In view of Applicant’s amendment, Claims 4 and 5 objected under 37 CFR § 1.75 as being a substantial duplicate thereof, is withdrawn.
IV. Response to Arguments 35 USC § 103 Rejections –
Rejection 1: Claims 1, and 16-17 stand rejected under 35 U.S.C. §103 as being allegedly unpatentable over US 3,974,281 to Gadekar ("Gadekar"); in view of SA Safavynia,; as evidenced by CAS Common Chemistry ("CAS") and PubChem CID 40632 ("PubChem").
Rejection 2: Claims 1 and 6-11 stand rejected under 35 U.S.C. §103 as being allegedly unpatentable over Gadekar; in view of Safavynia; and further in view of D. Dutta, et. al "Neuroprotective effect of pirfenidone on scopolamine induced cognitive dysfunction.
Applicant' s arguments, filed 03/02/2026, with respect to the rejection(s) above, have been fully considered and are persuasive. Therefore, the rejection has been withdrawn.
However, upon further consideration, a new ground(s) of rejection is made.
V. Second (2nd) Non-Final Rejection –
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Graham v. Deere, Test for Obviousness
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.
Joint Inventors
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.
A. First Rejection -
Claims 1, 6-11 and 16-17 are rejected under 103 as being unpatentable over Tan (Biomed Res Int. 2021 Nov 26;2021:3883204; hereinafter “Tan”) in view of Bizargity (Transplantation. 2012;94:114; hereinafter “Bizargity”).
Tan teaches the status of the art in Post-Operative Cognitive Dysfunction (POCD) and a relationship between TNF-alpha and POCD. “Surgical trauma or anesthesia could increase the level of inflammatory cytokines in patients after surgery. Current studies on inflammation-related factors had focused on S100B protein, interleukin-6 (IL-6), interleukin-1β (IL-1β), interleukin-17 (IL-17), tumor necrosis factor-α (TNF-α), the complement system, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), prostaglandin E (PGE), and other factors (pg. 1, col. 2, section 2-POCD and Inflammation Factors).”
In subsection 2.5-Tumor Necrosis Factor α, Tan teaches that there are “so many studies proving the correlation between TNF-alpha and POCD”. At least some of the studies relate to mammals and these animal models are representative of human models. Tan further teaches (pg. 3, col. 1, para. 1).”
2.5. Tumor Necrosis Factor-α: TNF-α was a protein involved in the signaling of immune response cells, which could promote the inflammation. In the inflammatory response, TNF-α increased the production of other proinflammatory cytokines, such as IL-1, IL-6, and IL-8. TNF-α was also involved in many physiological processes in the central nervous system. The presence of a large number of cytokine receptors in the hippocampus during neuroinflammation made it susceptible to high concentrations of proinflammatory cytokines, such as TNF-α. Once these cytokine receptors were activated at high levels, the metabolic Glu2 receptors were downregulated to enhance the AMPA/NMDA signaling which could disrupt the LTP process. In addition, TNF-α restrained inhibitory neurotransmission by downregulating GABA receptors, disrupted the delicate balance between excitatory and inhibitory neurotransmission, and ultimately promoted the glutamate toxicity. It had contributed to the advancement of cognitive dysfunction. In these completed studies, isoflurane anesthesia increased the incidence of POCD in diabetic rats through the TNF-α-dependent mechanism. After undergoing elective head and neck cancer surgery under general anesthesia, the postoperative TNF-α level was obviously increased in the POCD group . The group with the highest TNF-α level had a significantly higher incidence of POCD than the control group undergoing unilateral hip replacement . Although there were so many studies proving the co-relationship between TNF-α and POCD, the mechanism by which TNF regulated the progression of POCD was still unclear.
Thus, there is at least a reasonable expectation of success that using a molecule that reduces TNF-alpha would lead to at least some impact on POCD in the models indicated, and by extension into those mammals that the models are there to represent.
Although the “the mechanism by which TNF regulated the progression of POCD” is unclear, that fails to undermine the correlation of “so many studies” which suggests that regulating TNF-alpha correlates with POCD. Thus, if one wanted to reduce POCD, reduction or modulation of TNF-alpha would be reasonably expected to reduce POCD regardless of the detail of the mechanism.
The schematic below (Figure 1) further supports the knowledge in the art and the linkage between TNF-alpha inhibition and cognitive decline. As seen at least in the top arrow, TNF-alpha leads to cognitive decline, so reducing TNF-alpha would be expected to reduce cognitive decline which is supported by so many studies in this correlation.
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As stated above, this figure shows the mechanistic impact of various cytokines on cognitive decline. Reduction of TNF-alpha based on the above mechanistic picture showing the status of the prior art, would be expected to reduce overall inflammation and reduce one of the causal drivers in POCD.
Tan fails to teach a molecule that inhibits TNF-alpha.
Bizargity teaches pirfenidone (PFD) inhibits cytokine production of specific cytokines, such as CSF-3, IL-10, MCP-1, CCL12 (MCP-5), soluble TNF receptor 1, and TNF-α. “PFD inhibits Dendritic Cells (DCs) cytokine production. As another measure of DC activation, we analyzed the effect of PFD on cytokine production of LPS-stimulated DCs. PFD inhibited the secretion of CSF-3, IL-10, MCP-1, CCL12 (MCP-5), soluble TNF receptor 1, and TNF-α, whereas there was no significant change in the levels of IL-6, IL-9, IL-12p40, IL-12p70, or regulated on activation normal T-cell expressed and secreted (Fig. 4B). This data showed that PFD selectively inhibits cytokine release from stimulated DCs (pg. 115, col. 2, para. 3).
It would have been prima facie obvious to use a TNF-alpha inhibitor to treat Post-Operative Cognitive Dysfunction (POCD) because it is linked to the mechanism driving cognitive decline in a POCD patient population. Bizargity teaches PFD is known to reduce various inflammatory markers, including TNF-α. Thus, applying a known drug that inhibits TNF-α to a known disease, POCD, that is linked to TNF-α as being at correlated to the disease, one would have a reasonable expectation of success in treating POCD because both the drug and the disease are linked through reduction of inflammatory markers such as TNF-α.
B. Second Rejection -
Claim(s) 1, 6-11 and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over S. Gadekar in US 3,974,281 (hereinafter “Gadekar”) as evidenced by CAS Common Chemistry (Pirfenidone; hereinafter “CAS”) and PubChem (Pirfenidone - PubChem CID 40632; hereinafter “PubChem”).
With respect to Claims 1, 6-11 and 16-17, Gadekar teaches a method for the treatment of post-operative cognitive dysfunction. In Gadekar, analgesic testing in animals with its hind limb inflamed is based on the absence of a squeal in response to flexion of the inflamed ankle joint using 5-methyl-1-phenyl-2-(1H)-pyridone, which as evidenced by CAS Common Chemistry (Claim 12 and 13; col. 1, lns. 55-60) and PubChem is pirfenidone and Applicant’s election (abstract; col. 1, lns. 14-29; Novel analgesic, anti-pyretic, anti-inflammatory compositions containing the active ingredient the compound, 5-methyl-1-phenyl-2-(1H)-pyridone… are known to possess analgesic, qualities to be effective in the treatment of a number of upper respiratory ailments (as defined by the Instant Specification, pg. 7, as “some studies have presented the hypothesis that neuroinflammation is a factor that relates to cognitive decline after surgery; which reads on treatment for post-operative cognitive dysfunction).
The effectiveness of pirfenidone (a.k.a. AMR-69, 5-methyl-1-phenyl-2-(1H)-pyridone) comprises administering to a human or other mammal (abstract; col. 1, lns. 14-29; in humans and other mammals...) an effective amount of one or more compounds selected from the group consisting of N-substituted-2(1H)-pyridines, N-substituted-3(1H)-pyridines (col. 2, lns. 3-16; col. 2, lns. 60-70; col. 5, lns. 48-65; shows analgesic and anti-inflammatory activity). The treatment effectiveness of AMR-69 afforded protection against focal respiratory tract pathology (petechiae, edema, hemorrhage, focal infection) upon gross examination of rat lung tissues and microscopic examination of dog lung tissues following treatment. All which indicate breathing treatment to protect mucous membranes against deadly agent causing cognitive decline (col. 6, lns. 30-40).
With respect to Claim 6-8, Gadekar teaches the following dosages:
Claim 6: wherein a dosage from about 10 mg to about 500 mg/kg of body weight per day (col. 14, claim 1: dosage is 100-500 mg, col. 14, claim 2: dosage is 300-400 mg, col. 14, claim 6: dosage is 100-500 mg, col. 14, claim 7: dosage is 300-400mg; indicating a range of total 100-500 mg which overlap with the instant range; col. 9, lns. 13-29: oral median analgesic dose (ED50) in rats is 145± 26 mg/kg: giving a range of 119-171 mg/kg-indicating an overlapping range with the claim; col. 9, lns. 29-36: anti-inflammatory oral effective dose (ED50) in rats is 200± 46 mg/kg: giving a range of 154-246 mg/kg-indicating an overlapping range with the claim).
Claim 7: wherein a dosage of from about 20 mg to about 150 mg/kg of body weight per day of one or more of said compounds in total (col. 14, claim 1: dosage is 100-500 mg, col. 14, claim 2: dosage is 300-400 mg, col. 14, claim 6: dosage is 100-500 mg, col. 14, claim 7: dosage is 300-400mg; indicating a range of total 100-500 mg which overlap with the instant range; col. 9, lns. 13-29: oral median analgesic dose (ED50) in rats is 145± 26 mg/kg: giving a range of 119-171 mg/kg-indicating an overlapping range with the claim; col. 9, lns. 29-36: anti-inflammatory oral effective dose (ED50) in rats is 200± 46 mg/kg: giving a range of 154-246 mg/kg-indicating a close range with the claim).
Claim 8: wherein administration is about 20 to 3,000 mg per dose to humans (col. 14, claim 1: dosage is 100-500 mg, col. 14, claim 2: dosage is 300-400 mg, col. 14, claim 6: dosage is 100-500 mg, col. 14, claim 7: dosage is 300-400mg; indicating a range of total 100-500 mg which overlap with the instant range; col. 13, lns. 35-63 to col. 14, lns. 1-10, Example 30: Therapeutic dosage form of 5-methyl- l-phenyl-2-(1H)-pyridone made in 100-500 mg tablets).
Therefore it would be obvious to use the Gadekar since dose is a concentration, it is customary through routine optimization to determine for a specific composition what is considered a low dose or doses that are less of the half-lethal does, absent of unexpected or superior results. MPEP § 2144.05.II.
One would also be motivated to use known doses of a molecule deemed safe and effective by the FDA. However, it would have been prima facie obvious to one having ordinary skill in the art to arrive at an overlapping range because according to MPEP 2144.05
Overlapping ranges:
In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of “about 1-5%” while the claim was limited to “more than 5%.” The court held that “about 1-5%” allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of “50 to 100 Angstroms” considered prima facie obvious in view of prior art reference teaching that “for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms].” The court stated that “by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range.”).
Conclusions
Claims 1, 6-11 and 16-17 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Josmalen M. Ramos-Lewis whose telephone number is (571)272-0084. The examiner can normally be reached M-F 9:00-5:30 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton A. Brooks can be reached on (571)270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Josmalen M. Ramos-Lewis, Ph.D.
Patent Examiner
Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
Prosecution Insights