DETAILED ACTION
This action is in response to papers filed on 10/30/2025. Claims 1-2, 7-11, and 22-24 of Ambati et al., 17799149 (08/11/2022) are pending examination on the merits: claims 1, and 7-10 are amended. Claims 1-2, 7-11, and 22-24 are rejected.
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/US2021/017663 02/11/2021) which claims benefit of 62/972,848 (02/11/2020).
Withdrawn Rejections/Objections
The following have been withdrawn:
The rejections of claims 8 and 10 under 35 U.S.C. 112(b) are withdrawn in view of Applicant’s amendment to claim 8, and correction of claim 10 dependency. Applicant’s Remarks at page 9.
Modified Claim Rejections - 35 USC § 112
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.
Claims 1-2, 7-11, and 22-24 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 treating macular degeneration… comprising administering… fluoxetine, does not reasonably provide enablement for inhibiting the development of macular degeneration in a subject, or the treatment and/or inhibiting the development of essentially all diseases, disorder, and/or condition associated with NLRP3-ASC inflammasome activation in a subject in need thereof. 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.
To be enabling, the specification of the patent 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, 1561 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
Factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue” include, but are not limited to:
(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.
MPEP. § 2164.01(a); In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988); In re Wright, 999 F.2d 1557, 27 USPQ2d 1510 (Fed. Cir. 1993).
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention, state and predictability of the art, and relative skill level
The invention relates to the methods for treating and/or inhibiting: 1) the development of macular degeneration; 2) the development of a disease, disorder, and/or condition associated with NLRP3-ASC inflammasome activation; and 3) RPE degeneration associated with NLRP3-ASC inflammasome activation in a subject in need thereof, the method comprising administering to the subject one or more doses of fluoxetine. These diseases and disorders include Alzheimer’s Disease, amyotrophic lateral sclerosis, autism spectrum disorder, pulmonary tuberculosis, anxiety disorders, hepatitis, Parkinson’s disease, cancer, systemic lupus erythematosus, obesity, allergic asthma, traumatic brain injury, among others.
However, the state of the art recognizes that some claimed cognitive disorders, such as Alzheimer’s Disease, are not curable. Arafah et al., The Future of Precision Medicine in the Cure of Alzheimer’s Disease. Biomedicines, 11(2), 335 states that, “There is no cure for Alzheimer’s, but medications and other therapies can help manage symptoms and improve quality of life” (p. 4). Arafah et al., also discloses that condition isn’t always preventable as “preventative measures of neurodegenerative illnesses based on unique physiological characteristics” (p. 8).
Li et al., Front. Immunol., 06 April 2025 Sec. Inflammation Volume 16 - 2025 teaches that “… NLRP3 inflammasome plays a pivotal role in the pathogenesis of Alzheimer’s disease by driving neuroinflammation, Aβ accumulation, tau pathology, and neuronal damage…” (Conclusion), and that while “The NLRP3 inflammasome, a key mediator of neuroinflammation, has emerged as a critical player in AD pathogenesis…” for example, there is still no cure for the disease. Abstract. Li also discusses that “Therapeutic strategies targeting the NLRP3 inflammasome, such as IL-1β inhibitors, natural compounds, and novel small molecules, are discussed as promising approaches to mitigate neuroinflammation and slow AD progression…”, further reiterating no absolute cure for the disease. To one of ordinary skill in the art, the association NLRP3 inflammasome with AD is clearly not equivalent to curing the disease.
The relative skill of those in the art is high, that of an MD or PHD. That factor is outweighed, however, by the unpredictable nature of the art. As illustrative of the state of the art, the examiner cites the fact that while Applicant demonstrated fluoxetine’s modulating effects on certain proteins (for e.g., Specification, Example 1, page 44), nowhere in the Specification did Applicant demonstrate a method of inhibiting the development of any of the laundry list of diseases including Alzheimer’s Disease. Given the complexities around treating and inhibiting the development of Alzheimer’s Disease (AD), the Examiner maintains that Applicant has yet to enable the methods for treating and/or inhibting: 1) the development of macular degeneration; 2) the development of a disease, disorder, and/or condition associated with NLRP3-ASC inflammasome activation; and 3) the RPE degeneration associated with NLRP3-ASC inflammasome activation in a subject in need thereof, the method comprising administering to the subject one or more doses of fluoxetine, wherein said diseases and/or disorders include diseases and/or disorders such as Alzheimer’s Disease, amyotrophic lateral sclerosis, autism spectrum disorder, pulmonary tuberculosis, anxiety disorders, hepatitis, Parkinson’s disease, cancer, systemic lupus erythematosus, among others.
Additionally, the examiner contends that the method for treating and/or inhibiting: 1) the development of macular degeneration; 2) the development of a disease, disorder, and/or condition associated with NLRP3-ASC inflammasome activation; and 3) RPE degeneration associated with NLRP3-ASC inflammasome activation in a subject in need thereof, the method comprising administering to the subject one or more doses of fluoxetine, encompasses various types of patentably indistinct diseases and/or disorders. Applicant has failed to provide enablement for the scope of diseases and inhibiting the development of the multitude of diseases and disorders. Further, the predictability of treating cognitive disorders like AD is relatively low given that the various types of ADs have different causative agents, involve different cellular mechanisms, and consequently, differ in treatment protocol as discussed by Arafah et al. It is known (see Athanasios et al., Frontiers in Neuroscience,13, 2019, pp. 1-5) in the current art that the challenge of treating AD is related to the multidimensionality of biomarkers, risk factors, and the pathophysiological mechanisms of AD. Thus, given that applicant has failed to demonstrate treatment or prevention of Alzheimer’s Disease, and in light of the challenge in treating said AD, the examiner maintains that Applicant has not enabled the breadth of the claims.
One skilled in the art would not reasonably expect that one agent (i.e., fluoxetine) would be effective in treating or inhibiting the development of the claimed list of diseases and/disorders, including AD, based on the current arts, and the instant Specification.
The amount of guidance or direction needed to enable the invention is inversely related to the degree of predictability in the art. In re Fisher, 839, 166 USPQ 24. Thus, although a single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements, in cases involving unpredictable factors, such as most chemical reactions and physiological activity, more teaching or guidance is required. In re Fisher, 427 F.2d 839, 166 USPQ 24; Ex Parte Hitzeman, 9 USPQ 2d 1823. For example, the Federal Circuit determined that, given the unpredictability of the physiological activity of RNA viruses, a specification requires more than a general description and a single embodiment to provide an enabling disclosure for a method of protecting an organism against RNA viruses. In re Wright, 999 F.2d 1562-63, 27 USPQ2d 1575.
The breadth of the claims
The claims are thus very broad insofar as they recite the methods for treating and/or inhibiting: the development of a multitude of disease, disorder, and/or condition associated with NLRP3-ASC inflammasome activation; wherein the disease, disorder and/or condition includes a wide range of diseases and disorders such as Alzheimer’s Disease, amyotrophic lateral sclerosis, autism spectrum disorder, pulmonary tuberculosis, anxiety disorders, hepatitis, Parkinson’s disease, cancer, systemic lupus erythematosus, among others.
The amount of direction or guidance provided and the presence or absence of working examples
The specification provides no direction or guidance for treating and/or inhibiting the development of a multitude of disease, disorder, and/or conditions associated with NLRP3-ASC inflammasome activation; wherein the disease, disorder and/or condition includes a wide range of diseases and disorders such as Alzheimer’s Disease, amyotrophic lateral sclerosis, autism spectrum disorder, pulmonary tuberculosis, anxiety disorders, hepatitis, Parkinson’s disease, cancer, systemic lupus erythematosus, among others. No reasonably specific guidance is provided concerning useful therapeutic protocols for treating or preventing ADs, for example. While Applicant demonstrated fluoxetine’s modulating effects on certain proteins (for e.g., Specification, Example 1, page 44), the Specification is overly generalized and draws generalized conclusion without any support. For example, in Example 4, Applicant claims Fluoxetine use is associated with reduced development of dry macular degeneration among people diagnosed with clinical depression based on the health care claim data obtained on patients with commercial health insurance. Applicant’s Table 1:
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Applicant concluded that Fluoxetine use was associated with a reduction in the hazard of developing dry macular degeneration, and claims a method of treating and/or inhibiting the development of a multitude of diseases and disorders. Additionally, no working example of disease inhibition has been supplied.
The quantity of experimentation necessary
Because of the known unpredictability of the art, and in the absence of experimental evidence, no person skilled in the art would accept the assertion that the instantly claimed methods could be predictably used for, for example, the inhibition of the development of AD, or the treatment of said disease(s) inferred by the claims and contemplated by the specification. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is “undue”, not “experimentation”.
Applicant’s Arguments
Applicant contends that Examples 1 and 2 teach the fluoxetine inhibits inflammasome activation, Example 3 teaches that fluoxetine inhibits Alu RNA-induced RPE degeneration in vivo in mice, and that there is an association between fluoxetine use and reduced development of dry macular degeneration among people diagnosed with clinical depression in Example 4 based on commercial data, Example 5 shows enantiomers of fluoxetine are more effective in reducing RPE degeneration than a racemic mixture of fluoxetine, and that amyloid Beta-induced RPE degeneration in mice is inhibited by fluoxetine in Example 6. Applicant’s Remarks at page 7.
From the examples, Applicant contends that the diseases and disorders recited by the claims and contemplated by the Specification, although varying in etiology, are all associated with NLRP3-ASC inflammasome activation, and fluoxetine is shown to inhibit NLRP3-ASC inflammasome; thus, essentially, any and all diseases and/or disorders associated with NLRP3-ASC inflammasome, is treatable by and their development inhibitable by the claimed method. Applicant’s Remarks at pages 7-8.
Examiner’s Response
Applicant’s arguments are acknowledged and have been fully considered, but are not found to be persuasive in view of the modified rejection discussed above. Moreover, while the Specification provides some support for the specific subject-matter demonstrated in Examples 1-5, the evidence of record does not reasonably enable the full scope of the claimed method, particularly the treatment of any and all diseases or disorders associated with NLRP3-ASC inflammasome activation by administering fluoxetine.
Applicant also relies on several examples that show particular effects of fluoxetine in limited experimental contexts, including inhibition of inflammasome activation, reduction of Alu RNA-induced RPE degeneration in mice, and epidemiological association data. However, these examples are directed to specific biological models, disease states, and experimental conditions. The data do not reasonably demonstrate that the claimed method is operable across the full breadth of diseases and disorders recited, which encompass a wide variety of conditions with distinct etiologies, tissue types, and pathological mechanisms.
The Specification generalizes from a small number of experimental models to conclude that any disorder associated with NLRP3-ASC inflammasome activation is treatable by the claimed method. This conclusion is not reasonably supported because:
Substantial Diversity of Claimed Conditions
Diseases associated with NLRP3-ASC inflammasome activation include numerous unrelated conditions across different organ systems (e.g., neurodegenerative, metabolic, autoimmune, and cardiovascular diseases). These conditions differ significantly in pathophysiology, disease drivers, progression, and treatment requirements. Evidence showing efficacy in one or a few models does not reasonably establish efficacy across this entire spectrum.
Lack of Representative Examples
The Specification provides only a limited number of experimental examples, largely focused on retinal or related inflammatory models. There is no demonstration or reasonably predictive data for many other claimed disorders. The limited examples are not representative of the full scope of the claims.
Absence of Guidance for Broader Application
The Specification does not provide sufficient working examples, dosing guidance, or mechanistic evidence to enable a person of ordinary skill in the art to treat the full range of claimed diseases without undue experimentation. The disclosure lacks specific protocols, therapeutic windows, or predictive markers applicable across the full breadth of conditions.
Unpredictability of the Art
The treatment of complex, multi-factorial diseases, especially across different tissues and organ systems, is generally considered an unpredictable art. Even if a compound affects a shared inflammatory pathway, this does not establish that it will produce a therapeutically meaningful effect in all diseases associated with that pathway.
Accordingly, while the Specification may support the narrower scope demonstrated in the specific examples, it is erroneous to conclude that the disclosure enables a method for treating any and all diseases or disorders associated with NLRP3-ASC inflammasome activation. The current record does not provide sufficient evidence or guidance to enable the full scope of the claimed subject matter without undue experimentation. The rejection is therefore maintained.
Maintained Claim Rejections - 35 USC § 112
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 9, 11, 22, and 24 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.
Claims 9, 11, 22 and 24 recite the term substantially. The term substantially is a relative term which renders the claim indefinite. The term is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The Specification simply states on page 27:
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The requisite degree is not entirely clear because, for example, it is unclear whether 10% fluoxetine would be considered substantially pure when compared to 99% fluoxetine? Clarification is requested.
Applicant’s Arguments
Applicant contends that the term “substantially” is used in the context of fluoxetine in a substantially enantiomerically pure form, and that the term denotes that one enantiomeric form or the other is present in a composition in an amount of more than 75% by weight. Applicant argues that the phrase is specifically defined and is not indefinite.
Examiner’s Response
Applicant’s arguments are acknowledged, but are not found to be persuasive in view of the rejection above. As discussed above, the Specification on page 27 provides a wide range from about 10% to about 99% when defining the phrase substantially pure. However, there’s no standard for ascertaining the requisite degree without ambiguity. The rejection is maintained.
Modified 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.
Claims 1-2, 9-11, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Palczewski et al., US PG-PUB 2014/0235562 A1, (“Palczewski”) in view of Piipo et al., University of Eastern Finland (2019) (“Piipo”), and Du et al., International Journal of Neuropsychopharmacology, Volume 19, Issue 9, September 2016 (“Du”).
Regarding claim 1, Palczewski teaches a method for treating and/or inhibiting development of macular degeneration in a subject in need thereof (Para[0140]: "In some embodiments, the disclosed methods maybe combined with other methods for treating or preventing macular degeneration"), but does not expressly disclose the method comprising administering to the subject one or more doses of fluoxetine in an amount and via a route sufficient to treat or inhibit development of macular degeneration in the subject.
However, Palczewski discloses that fluoxetine may be used in the treatment of macular degeneration (Para [0111] "agents used to treat an ocular disorder associated with light induced retinal degeneration, aberrant all-trans-RAL clearance and/or ROS production can include Gs or Gq coupled serotonin receptor antagonists” and Para [0112] “In one embodiment, the serotonin receptor antagonist is selected from...fluoxetine").
Moreover, Piipo teaches in the Abstract on pages 7-8 that “… impaired cellular degradation activates the NLRP3 inflammasome in RPE cells via increased oxidative stress. RPE cells play a major role in the pathogenesis of AMD…” (age-related macular degeneration).
Du teaches that “fluoxetine significantly suppressed NLRP3 inflammasome activation” (Abstract). Du also teaches a method of treatment whereby “in vivo data showed that fluoxetine also suppressed NLRP3 inflammasome activation in hippocampus and macrophages of chronic mild stress mice and alleviated chronic mild stress-induced depression-like behavior” (Abstract; see, also Table 1). The animals were treated with fluoxetine at 10 mg/kg/d i.p according to Du at page 3. “In conclusion, our study demonstrates that fluoxetine suppresses CMS-induced NLRP3 inflammasome activation in the hippocampus and in BMDMs, accompanied by improvement of depressive behavior”. Du at page 7.
It would have therefore been prima facie obvious to one of skill in the art, before the effective filing date of the claimed invention, to combine the teachings and identify a method comprising administering to the subject one or more doses of fluoxetine in an amount and via a route sufficient to treat or prevent development of macular degeneration in the subject to treat macular degeneration by routine experimentation and arrive at the claimed invention. One would have been motivated to do so because: Palczewski teaches that fluoxetine may be used in the treatment of macular degeneration, including age related macular degeneration (para [0005], and Palczewski claim 20), Piipo teaches the mechanism by which this is possible in terms of impaired cellular degradation activating the NLRP3 inflammasome in RPE cells via increased oxidative stress, and that RPE cells play a major role in the pathogenesis of age-related macular degeneration, and Du teaches the inhibition of this inflammatory mechanism that “fluoxetine significantly suppressed NLRP3 inflammasome activation” (Abstract).
The combination of references would have allowed for one of ordinary skill in the art to arrive at the claimed invention with reasonable expectation of success. Additionally, obviousness does not require absolute predictability, but a reasonable expectation of success. See MPEP 2143.02. Claim 1 is therefore obvious over Palczewski, Piipo and Du.
Regarding claim 2, and as applied above to claim 1, Palczewski’s, Piipo and Du’s teachings are discussed. While Palczewski does not expressly disclose wherein the macular degeneration is dry macular degeneration in the method, Palczewski discloses that the ocular disorder being treated may be dry macular degeneration (Para [0100] "Macular degeneration is a form of retinal neurodegeneration, which attacks the macula and destroys high acuity vision in the center of the visual field. AMD can be in a dry form…”). Therefore, it would have also been obvious to one of skill in the art to further identify wherein the macular degeneration is dry macular degeneration, and to treat dry macular degeneration by routine experimentation using the method of claim 1. Claim 2 is therefore also obvious.
Regarding claim 9, Palczewski teaches a method for inhibiting and/or treating RPE degeneration in a subject in need thereof (Para [0140] "In some embodiments, the disclosed methods may be combined with other methods for treating or preventing macular degeneration", treatment of macular degeneration prevents RPE degeneration see instant claim 10), but does not disclose the method comprising introducing into the eye, retina, and/or RPE of the subject an effective amount of a composition comprising fluoxetine, optionally wherein the composition comprises fluoxetine in a substantially enantiomerically pure form. However, Palczewski discloses that fluoxetine may be used in the treatment of macular degeneration (Para [0111] "agents used to treat an ocular disorder associated with light induced retinal degeneration, aberrant all-trans-RAL clearance and/or ROS production can include Gs or Gq coupled serotonin receptor antagonists and Para [0112] "In one embodiment, the serotonin receptor antagonist is selected from ... fluoxetine"). Furthermore, Palczewski discloses that R-fluoxetine may be used (Para [0111] "Examples of serotonin receptor antagonists are citalopram, escitalopram, fluoxetine, R-fluoxetine").
Regarding the amendment: “wherein the RPE degeneration is associated with NLRP3-ASC inflammasome activation in the subject…”, Palczewski does not expressly teach this.
Piipo teaches in the Abstract on pages 7-8 that “… impaired cellular degradation activates the NLRP3 inflammasome in RPE cells via increased oxidative stress. RPE cells play a major role in the pathogenesis of AMD…”.
Du teaches that “fluoxetine significantly suppressed NLRP3 inflammasome activation” (Abstract). Du also teaches a method of treatment whereby “in vivo data showed that fluoxetine also suppressed NLRP3 inflammasome activation in hippocampus and macrophages of chronic mild stress mice and alleviated chronic mild stress-induced depression-like behavior” (Abstract; see, also Table 1). The animals were treated with fluoxetine at 10 mg/kg/d i.p according to Du at page 3. “In conclusion, our study demonstrates that fluoxetine suppresses CMS-induced NLRP3 inflammasome activation in the hippocampus and in BMDMs, accompanied by improvement of depressive behavior”. Du at page 7.
It would have been prima facie obvious to one of skill in the art, before the effective filing date of the claimed invention, to combine Palczewski method for inhibiting and/or treating RPE degeneration in a subject in need thereof comprising introducing into the eye, retina, and/or RPE of the subject an effective amount of a composition comprising fluoxetine, optionally wherein the composition comprises fluoxetine in a substantially enantiomerically pure form to inhibit retinal pigmented epithelium degeneration by routine experimentation, and wherein the RPE degeneration is associated with NLRP3-ASC inflammasome activation in the subject, because Palczewski teaches that fluoxetine may be used in the treatment of macular degeneration, including age related macular degeneration (para [0005], and Palczewski claim 20), Piipo teaches the mechanism by which this is possible in terms of impaired cellular degradation activating the NLRP3 inflammasome in RPE cells via increased oxidative stress, and that RPE cells play a major role in the pathogenesis of age-related macular degeneration, and Du teaches the inhibition of this inflammatory mechanism that “fluoxetine significantly suppressed NLRP3 inflammasome activation” (Abstract). One would have been motivated to do so because Palczewski teaches a method for inhibiting and/or treating RPE degeneration in a subject in need thereof using fluoxetine whereby fluoxetine inhibits NLRP3-ASC inflammasome activation and is thus expected to treat AMD per Piipo and Du’s teachings. See In re Aller, 220 F.2d 454,456, 105 USPQ 233,235 (CCPA 1955) which states, "where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." See, also MPEP § 2144.05. Additionally, obviousness does not require absolute predictability, but a reasonable expectation of success. See MPEP 2143.02. Therefore, claim 9 is also obvious.
Regarding claim 10, Palczewski in view of Piipo and Du teaches the method of claim 9, wherein the RPE degeneration is associated with age-related macular degeneration (AMD), optionally dry AMD.
Palczewski also discloses that the ocular disorder being treated may be dry macular degeneration (Para [0100] "Macular degeneration is a form of retinal neurodegeneration, which attacks the macula and destroys high acuity vision in the center of the visual field. AMD can be in a dry form").
Therefore, it would have also been obvious to one of skill in the art to identify wherein the RPE degeneration is associated with dry AMD to treat dry AMD by routine experimentation, as discussed and applied above to claim 9. Claim 10, as is claim 9, is therefore also obvious.
Regarding claim 11, and as applied above to claim 1, Palczewski, Piipo and Du’s teachings are discussed. While Palczewski’s does not expressly teach, “wherein the fluoxetine is substantially enantiomerically pure R-fluoxetine or substantially enantiomerically pure S-fluoxetine”, the recitation of substantially enantiomerically pure R-fluoxetine or S-fluoxetine suggests that a racemic mixture containing both stereoisomers is also effective, and would have been obvious to one of ordinary skill in the art based on Palczewski’s teachings in at least, para [0043]: “It will be noted that the structure of some of the compounds of the application include asymmetric (chiral) carbon atoms. Moreover, Palczewski discloses that R-fluoxetine may be used (Para [0111] "Examples of serotonin receptor antagonists are citalopram, escitalopram, fluoxetine, R-fluoxetine"), and that “it is to be understood accordingly that the isomers arising from such asymmetry are included within the scope of the invention…” (Palczewski at page 5).
Therefore, it would have also been obvious to one of skill in the art to identify wherein the fluoxetine is substantially enantiomerically pure R-fluoxetine to treat macular degeneration by routine experimentation. One of ordinary skill would be motivated to identify both the R and S enantiomers of fluoxetine and arrive at the claimed invention, because Palczewski’s teachings teach and/or suggest the method of claim 1, as disclosed above, by administering R-fluoxetine in one or more doses to a subject with macular degeneration. Routine optimization, by one of ordinary skill in the art, to identify the forms of isomers would have been obvious as a way to further optimize the effectiveness of the method of treatment, and arrive at the limitation successfully. See In re Aller, 220 F.2d 454,456, 105 USPQ 233,235 (CCPA 1955) which states, "where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." See, also, MPEP § 2144.05. Claim 11 is therefore also obvious.
Regarding claim 24, and as applied above to claim 9, Palczewski, Piipo and Du’s teachings are discussed. While Palczewski’s does not expressly teach, “wherein the fluoxetine is substantially enantiomerically pure R-fluoxetine or substantially enantiomerically pure S-fluoxetine”, the recitation of substantially enantiomerically pure R-fluoxetine or S-fluoxetine suggests that a racemic mixture containing both stereoisomers is also effective, and would have been obvious to one of ordinary skill in the art based on Palczewski’s teachings in at least, para [0043]: “It will be noted that the structure of some of the compounds of the application include asymmetric (chiral) carbon atoms. Moreover, Palczewski discloses that R-fluoxetine may be used (Para [0111] "Examples of serotonin receptor antagonists are citalopram, escitalopram, fluoxetine, R-fluoxetine"), and that “it is to be understood accordingly that the isomers arising from such asymmetry are included within the scope of the invention…” (Palczewski at page 5).
Therefore, it would have also been obvious to one of skill in the art to identify wherein the fluoxetine is substantially enantiomerically pure R-fluoxetine according to the method of claim 9 by routine experimentation. One of ordinary skill would be motivated to identify both the R and S enantiomers of fluoxetine and arrive at the claimed invention, because Palczewski’s teachings teach and/or suggest the method of claim 9, as disclosed above, by administering R-fluoxetine to a subject in need thereof. Routine optimization, by one of ordinary skill in the art, to identify the forms of isomers would have therefore also been obvious, as a way to further optimize the effectiveness of the method of treatment, and arrive at the limitation successfully. See In re Aller, 220 F.2d 454,456, 105 USPQ 233,235 (CCPA 1955) which states, "where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." See, also, MPEP § 2144.05. Claim 24 is therefore also obvious.
Applicant’s Arguments
Applicant argues that Palczewski’s teachings are directed to light-induced retinal degeneration in an experimental model in animals where high intensity light induces death of retinal cells. Applicant argues that in humans with age-related macular degeneration, this is not what happens and thus the mechanism by which damage occurs in Palczewski is not relevant to the claimed subject matter. Applicant’s Remarks at page 10. Applicant further contends that there’s no experimental evidence in Palczewski that fluoxetine or any other serotonin receptor has any efficacy in treating light induced retinal damage, and thus one of ordinary skill would not have reasonably expected Palczewski teachings to enable one to arrive at the instant invention successfully. Applicant’s Remarks at page 10.
Examiner’s Response
Applicant’s arguments are acknowledged, and have been fully considered, but are not found to be persuasive in view of the modified rejection above necessitated by Applicant’s amendments. Claims 1-2, 9-11, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Palczewski et al., US 20140235562 A1, (“Palczewski”), in view of Piipo et al., University of Eastern Finland (2019) (“Piipo”), and Du et al., International Journal of Neuropsychopharmacology, Volume 19, Issue 9, September 2016, (“Du”). The rejection is maintained.
Claims 7-8, 22 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Du et al., International Journal of Neuropsychopharmacology, Volume 19, Issue 9, September 2016, (“Du”)
Regarding claim 7, Du teaches that NLRP3 inflammasome-induced inflammation plays a crucial role in the pathogenesis of depression, and teaches that “fluoxetine significantly suppressed NLRP3 inflammasome activation” (Abstract). Du also teaches a method of treatment whereby “in vivo data showed that fluoxetine also suppressed NLRP3 inflammasome activation in hippocampus and macrophages of chronic mild stress mice and alleviated chronic mild stress-induced depression-like behavior” (Abstract; see, also Table 1). The animals were treated with fluoxetine at 10 mg/kg/d i.p according to Du at page 3. “In conclusion, our study demonstrates that fluoxetine suppresses CMS-induced NLRP3 inflammasome activation in the hippocampus and in BMDMs, accompanied by improvement of depressive behavior”. Du at page 7.
It would have therefore been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to identify a method of treating and/or inhibiting development of a disease, disorder, and/or condition associated with NLRP3-ASC inflammasome activation in a subjected in need thereof, the method comprising administering to the subject one or more doses of fluoxetine in an amount and via a route sufficient to treat or prevent development of the disease, disorder, and/or condition in the subject, wherein the disease is depression for example in view of Du’s teachings. One would have been motivated to do so because Du teaches that “fluoxetine confers an antidepressant effect partly through inhibition of peripheral and central NLRP3 inflammasome activation and suggest the promising clinical use of fluoxetine in NLRP3 inflammasome driven inflammatory diseases such as depression…” Du at pages 7 and 8, and Fig. 6:
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Claim 7, is therefore obvious over Du.
Regarding claim 8, Du teaches the method according to claim 7. Du also teaches wherein the disease, disorder, and/or condition associated with NLRP3-ASC inflammasome activation is, for example, depression. Du also teaches that “NLRP3 inflammasome has been found to be activated in patients with major depressive disorder…”. Therefore, it would have been obvious to identify a method of treating and/or inhibiting development of a disease, disorder, and/or condition associated with NLRP3-ASC inflammasome activation in a subjected in need thereof, the method comprising administering to the subject one or more doses of fluoxetine in an amount and via a route sufficient to treat or prevent development of the disease, disorder, and/or condition in the subject, wherein the disease is depression, more particularly, major depressive disorder, in view of Du’s teachings. One would have been motivated to do so because Du teaches that “fluoxetine confers an antidepressant effect partly through inhibition of peripheral and central NLRP3 inflammasome activation and suggest the promising clinical use of fluoxetine in NLRP3 inflammasome driven inflammatory diseases such as depression…” Du at pages 7 and 8. Moreover, "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). Additionally, obviousness does not require absolute predictability, but a reasonable expectation of success. See MPEP 2143.02. Claim 8 is obvious.
Regarding claim 22, Du teaches the method according to claim 7. While Du does not expressly teach, “wherein the fluoxetine is substantially enantiomerically pure R-fluoxetine or substantially enantiomerically pure S-fluoxetine”, the recitation of substantially enantiomerically pure R-fluoxetine or S-fluoxetine suggests that a racemic mixture containing both stereoisomers is also effective, and would have been obvious to one of ordinary skill in the art based on Du’s teachings. Du teaches said method, as disclosed above, by administering fluoxetine in one or more doses to a subject with a disease, disorder, and/or conditions associated with NLRP3 inflammasome activation. Routine optimization, by one of ordinary skill in the art, to identify the forms of isomers would have been obvious as a way to further optimize the effectiveness of the method of treatment, and arrive at the limitation successfully. See In re Aller, 220 F.2d 454,456, 105 USPQ 233,235 (CCPA 1955) which states, "where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." See, also, MPEP § 2144.05. Claim 22 is therefore also obvious.
Regarding claim 23, Du teaches the method according to claim 7. As disclosed in the Abstract, “… a chronic mild stress model and cultured primary macrophage/microglia to investigate the effects of fluoxetine on NLRP3 inflammasome and its underlying mechanisms” was used, with in vivo findings disclosing “… that fluoxetine also suppressed NLRP3 inflammasome activation in hippocampus and macrophages of chronic mild stress mice and alleviated chronic mild stress-induced depression-like behavior.”. Additionally, obviousness does not require absolute predictability, but a reasonable expectation of success. See MPEP 2143.02. Claim 23 is therefore also obvious over Du.
Applicant’s Arguments
Applicant argues that with respect to macular degeneration, blocking NLRP3 inflammasome activation could worsen macular degeneration, and cites Doyle et al., to show that NLRP3 plays a “protective role” in the progression of AMD. Applicant’s Remarks at page 11.
Examiner’s Response
Applicant’s arguments are acknowledged, and have been fully considered, but are not found to be persuasive. Applicant’s invention is directed to using fluoxetine to inhibit and/or treat a disease, disorder, and/or condition associated with NLRP3-ASC inflammasome activation (c.f., claims 7 and 9), which includes a broad list of diseases, disorders, and conditions. The prior arts cited above shows that fluoxetine operates by inhibiting NLRP3 Inflammasome Activation per Du’s teachings. The mechanism of action of fluoxetine modulating NLRP3 inflammasome activation does not switch on and off depending on the disease/disorder – if administered, fluoxetine acts on said NLRP3 inflammasome pathway per the teachings discussed above. Du also teaches in vivo findings disclosing “… that fluoxetine also suppressed NLRP3 inflammasome activation in hippocampus and macrophages of chronic mild stress mice and alleviated chronic mild stress-induced depression-like behavior.”. Additionally, obviousness does not require absolute predictability, but a reasonable expectation of success. See MPEP 2143.02. The rejection is maintained.
Modified 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 1-2, 7-11 and 22-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 6-15 of U.S. Patent No. 11730743 in view of Palczewski et al. US 20140235562, Piipo et al., University of Eastern Finland (2019) (“Piipo”), and Du et al., International Journal of Neuropsychopharmacology, Volume 19, Issue 9, September 2016, (“Du”).
Palczewski, Piipo and Du teachings are discussed above.
The claims are not patentably distinct because both disclose treating age-related macular degeneration comprising administering an inhibitor of MyD88 to a subject. The differences being that the instant claims encompass dry form and claim 1 of the ‘743 patent disclose wet form however, as discussed supra, Palczewski et al. disclose treating wet or dry AMD (para 0138). The drug of choice includes fluoxetine and fluoxetine is known to inhibit MyD88. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to administer fluoxetine to inhibit the dry form of AMD of the ‘743 patent as Palczweski et al. disclose both wet and dry forms are treatable with fluoxetine. Furthermore, fluoxetine is an inhibitor of IRAK-1 phosphorylation and is also an inhibitor of NLRP3 inflammasome.
Claims 1-2, 7-11 and 22-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4, 10, 13 and 14 of U.S. Patent No. 11883409 in view of Palczewski et al. US 20140235562, Piipo et al., University of Eastern Finland (2019) (“Piipo”), and Du et al., International Journal of Neuropsychopharmacology, Volume 19, Issue 9, September 2016, (“Du”).
Palczewski, Piipo and Du teachings are discussed above.
The claims are not patentably distinct because both disclose treating age-related macular degeneration comprising administering an inhibitor of MyD88 to a subject. The differences being that the instant claims recite fluoxetine and the ‘409 patent recites an inhibitor of MyD88 however, fluoxetine is a known inhibitor of MyD88. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to administer fluoxetine to inhibit the dry or wet form of AMD of the ‘409 patent as Palczewski et al. disclose both wet and dry forms are treatable with fluoxetine. Claims 13-14 of the ‘409 patent recite the subject is in need of treatment of dry or wet macular degeneration therefore administration of the fluoxetine to said subjects with a MyD88 inhibitor (fluoxetine) would include treatment of the cells as recited in claim 1 as retinal photoreceptors are also taught in Palczewski.
Claims 1-2, 7-11 and 22-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 9707235 in view of Palczewski et al. US 20140235562, Piipo et al., University of Eastern Finland (2019) (“Piipo”), and Du et al., International Journal of Neuropsychopharmacology, Volume 19, Issue 9, September 2016, (“Du”).
Palczewski, Piipo and Du teachings are discussed above.
The claims are not patentably distinct because both disclose treating macular degeneration comprising administering an inhibitor of NLRP3 inflammasome to a subject. The differences being that the instant claims recite fluoxetine and the ‘235 patent recites an inhibitor of NLRP3 inflammasome however, fluoxetine is a known an inhibitor of NLRP3 inflammasome. As discussed supra, Palczewski et al. disclose both wet and dry forms of macular degeneration are treatable with fluoxetine. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to administer fluoxetine (NLRP3 inflammasome) to treat dry macular degeneration as recited n claim 1 of the ‘235 patent.
Applicant’s Arguments
Applicant argues against Palczewski similarly to Applicant’s arguments discussed above. Applicant’s Remarks at page 12.
Examiner’s Response
Applicant’s arguments are acknowledged, and have been fully considered but are not found to be persuasive in view of the prior art teachings discussed above. In view of Palczewski, Piipo and Du teachings discussed above, the nonstatutory double patenting rejections are maintained in view of the modified rejections necessitated by Applicant’s amendments. The rejection is maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/C A/Examiner, Art Unit 1622 February 12, 2026
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622