DETAILED ACTION
Claims 1-3, 6-18, and 21-24 are rejected to and under examination
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 .
Drawings
The drawings are objected to because the group labels along the X-axis are vague regarding the subject group receiving the treatment and the treatment type. Please correct the labels for the A, B, C, and D groups along the X-axis to accurately reflect the subject (e.g. mice) as well as the conditions subjected to (e.g. GWI toxin exposure vs No GWI toxin exposure) and treatment received (e.g. treatment vs no treatment). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 1 is objected to because of the following informalities: “A method of treating of Gulf War Illness” should read A method of treating Gulf War Illness. Appropriate correction is required.
Claim 13 is objected to because of the following informalities: “wherein the administration of PPAR-y agonist and a nuclear factor erythroid 2-related factor 2 (Nrf2) agonist increases stamina, improve cognition, improve information seeking or a combination thereof in the subject” should read wherein the administration of PPAR-y agonist and a nuclear factor erythroid 2-related factor 2 (Nrf2) agonist increases stamina, improves cognition, improves information seeking or a combination thereof in the subject. Appropriate correction is required.
Claim 14 is objected to because of the following informalities: “A method of ameliorating one or more symptoms of ameliorating one or more symptoms of Gulf War illness or syndrome in a subject,” should read A method of ameliorating one or more symptoms of Gulf War illness or syndrome in a subject.
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 8, 9, 23, 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.
The metes and bounds of claims 8 and 23, and 9 and 24 are rendered uncertain by the phrases “wherein the therapeutically effective amount of pioglitazone is 0.1 mg to 0.4 mg/kg body weight per day” and “wherein the therapeutically effective amount of t-BHQ is 1.0 mg to 5.0 mg/kg body weight per day”, respectively, because it is not clear whether Applicant is claiming that the lower bounds of those ranges are meant to be weight-based doses or not. The lack of clarity renders the claims indefinite since the resulting claims do not clearly set forth the metes and bounds of the patent protection desired.
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.
Claim 10 is 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. In claim 10, “transcription factor modulators” is not defined in the specification with reasonable clarity as to what entities the applicant is intending to reference.
Vas-Cath Inc. V. Mahurka, 19 USPQ2d 1111, states that applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention, for purposes of the “written description” inquiry, is “whatever is now claimed” (See page 1117).
A review of the language of the claim indicates that these claims are drawn to “transcription factor modulators”. A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997). In Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B (1), the court states “An adequate written description of a DNA ... requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention”. Hence, an adequate written description of the ingredients requires more than a mere statement that it is a transcription factor modulator.
The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984). Accordingly, stating “comprising administering a therapeutically effective amount of one or more transcription factor modulators…”, in the absence of knowledge as to what constitutes transcription factor modulators, is not a description. In the instant case, on page 17, paragraph 20, Applicant discloses “transcription factor modulators” as well as “SP600125, pifithrin derivatives” as examples. However, “pifithrin derivatives” itself is a genus within the claimed genus of “transcription factor modulators” that has not been described sufficiently by a representative number of species by the Applicant, and “SP600125” is a species that it is not representative of transcription factor modulators as a whole.
There is a single species of the claimed genus disclosed that is within the scope of the claimed genus, i.e., SP600125.
The disclosure of a single disclosed species may provide an adequate written description of a genus when the species disclosed is representative of the genus. However, the present claim encompasses numerous species that are not further described. There is substantial potential for variability among the species.
One of skill in the art would not recognize from the disclosure that the applicant was in possession of the genus of what constitutes “transcription factor modulators”. The specification does not clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed (see Vas-Cath at page 1116).
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Claims 1-3, 6-18, and 21-24 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:
A method of treating of Gulf War illness or syndrome in a subject, the method comprising: administering to the subject in need thereof a therapeutically effective amount of pioglitazone or rosiglitazone and tert- butylhydroquinone (t-BHQ) or sulforaphane;
A method of ameliorating one or more symptoms of ameliorating one or more symptoms of Gulf War illness or syndrome in a subject, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a pioglitazone or rosiglitazone and tert- butylhydroquinone (t-BHQ) or sulforaphane; and
A method of effecting neuroprotection in a subject in need thereof, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a pioglitazone or rosiglitazone and tert- butylhydroquinone (t-BHQ) or sulforaphane.
Does not reasonably provide enablement for:
A method of treating of Gulf War illness or syndrome in a subject, the method comprising: administering to the subject in need thereof a therapeutically effective amount of any and all nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-y) agonists and any and all nuclear factor erythroid 2-related factor 2 (Nrf2) agonists
A method of ameliorating one or more symptoms of Gulf War illness or syndrome in a subject, the method comprising: administering to the subject in need thereof a therapeutically effective amount of any and all nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-y) agonists and any and all nuclear factor erythroid 2-related factor 2 (Nrf2) agonists
A method of inhibiting neurodegeneration in a subject in need thereof, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a pioglitazone or rosiglitazone and tert- butylhydroquinone (t-BHQ) or sulforaphane.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the Invention: The nature of the invention is complex in that claims 1-3, and 6-13 are drawn a method of treating of Gulf War illness or syndrome in a subject, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-y) agonist and a nuclear factor erythroid 2-related factor 2 (Nrf2) agonist. Claims 14, 17-18, 21-24 are drawn to a method of ameliorating one or more symptoms of ameliorating one or more symptoms of Gulf War illness or syndrome in a subject, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-y) agonist and a nuclear factor erythroid 2-related factor 2 (Nrf2) agonist. Claims 15-16 are drawn to a method of inhibiting neurodegeneration or effecting neuroprotection in a subject in need thereof, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-y) agonist and a nuclear factor erythroid 2-related factor 2 (Nrf2) agonist.
However, PPAR-gamma agonists and Nrf2 agonists, as claimed in independent claims 1, 14, and 15, are broad groups of compounds and not commensurate in scope with the enabling disclosure, wherein the Applicant teaches a small selection of species relative to the genus claimed, and “inhibiting neurodegeneration” as claimed in claim 15, is not an outcome that is able to be determined or guaranteed.
Breadth of the Claims: The claims are broad in that the claims are drawn to:
A method of treating of Gulf War illness or syndrome in a subject, the method comprising: administering to the subject in need thereof a therapeutically effective amount of any and all nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-y) agonists and any and all nuclear factor erythroid 2-related factor 2 (Nrf2) agonists;
A method of ameliorating one or more symptoms of ameliorating one or more symptoms of Gulf War illness or syndrome in a subject, the method comprising: administering to the subject in need thereof a therapeutically effective amount of any and all nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-y) agonists and any and all nuclear factor erythroid 2-related factor 2 (Nrf2) agonists; and
A method of inhibiting neurodegeneration (preventing a complex and multifactorial disease state) or effecting neuroprotection in a subject in need thereof, the method comprising: administering to the subject in need thereof a therapeutically effective amount of any and all nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-y) agonists and any and all nuclear factor erythroid 2-related factor 2 (Nrf2) agonists.
The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the Specification and Existence of Working Examples: The specification describes:
Utilizing select species of PPAR-gamma agonists (rosiglitazone and pioglitazone) and select species of Nrf2 agonists (t-BHQ and Sulforaphane), in various methods directed towards affecting Gulf-War illness and related symptoms; and
Improved behavior observed in rats when treat treated with pioglitazone and t-BHQ
However, no working examples are given for:
Using any other species of PPAR-gamma agonists or Nrf2 agonists. While it is noted that the applicant has shown some data for activity against Gulf-War Illness, or symptoms thereof, using select species of PPAR-gamma agonists (rosiglitazone and pioglitazone) and select species of Nrf2 agonists (t-BHQ and Sulforaphane), the Applicant is not enabled for use of PPAR-gamma agonists and Nrf2 agonists as a whole; or
Inhibition of neurodegeneration.
Predictability and State of the Art: The state of the art at the time the invention was made was unpredictable and underdeveloped. It is known in the art that:
Pioglitazone and rosiglitazone are agonists at the PPAR-gamma receptor, and that t-BHQ and sulforaphane activate the Nrf2 transcription factor. It is also known that these two pathways are able to affect inflammation in Gulf-War Illness and its symptoms.
Neurodegeneration can be caused by various mechanisms and diseases (Alzheimer’s Disease, Gulf-War Illness, Lou Gehrig’s Disease, Parkinson’s, Huntington’s disease)
However:
Any and all PPAR-gamma agonists and Nrf2 agonists cannot be assumed to take the place of the select species demonstrated by the applicant. Agonist activity can vary greatly and a compound merely classifying as an agonist does not necessarily translate into desired effectiveness.
Neurodegenerative mechanisms are not similar such that one compound with a given mechanism of action can universally affect all mechanisms of neurodegeneration.
Puhl, A.C. Mechanisms of peroxisome proliferator activated receptor γ
regulation by non-steroidal anti-inflammatory drugs, Nuclear Receptor Signaling, Vol. 13, no. 1, pp. 1-17 (Year: 2015) - explains that alternative compounds show a degree of agonism at the PPAR-gamma receptor, and that PPAR-gamma agonists can vary in potency, leading one in the art to conclude that they are not interchangeable.
Wolozin, B. Mechanisms of Neurodegenerative Disorders, JAMA Neurology, Vol. 57, no. 6, pp. 793-796 (Year: 2000) – explains that different neurodegenerative disorders have different underlying mechanisms.
Amount of Experimentation Necessary: The quantity of experimentation necessary to carry out the claimed invention is high, as the skilled artisan could not rely on the prior art or instant specification to teach the methods claimed directed towards using a composition comprising a PPAR-gamma agonist and Nrf2 to affect Gulf-War Illness and related symptoms in a subject in need thereof. In order to carry out the claimed invention, one of ordinary skill in the art would have to:
Determine efficacy of all compounds that have any PPAR-gamma or Nrf2 agonism activity in the Applicant’s methods, per claims 1, 14 and 15.
Determine that all species of PPAR-gamma agonists or Nrf2 agonists can affect the various mechanisms by which many different neurodegenerative disorders progress, per claim 15.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 1-3, 6-18, 21-24 are not considered to be fully enabled by the instant specification.
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.
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 1-3, 6-9, 11-15, 17-18, and 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over Keledjian, K. (The peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone, ameliorates neurofunctional and neuroinflammatory abnormalities in a ratmodel of Gulf War Illness), PLOS ONE, Vol. 15, no. 11 (Nov. 13, 2020), pp. 1-21), in view of
Zhang, J. (Tert-butylhydroquinone Post-treatment Attenuates Neonatal Hypoxic-ischemic Brain Damage in Rats), Neurochem Int., Vol. 116, (June, 2018), pp. 1-12),
further in view of
Shetty, G.A. (Chronic Oxidative Stress, Mitochondrial Dysfunction, Nrf2 Activation and Inflammation in the Hippocampus Accompany Heightened Systemic Inflammation and Oxidative Stress in an Animal Model of Gulf War Illness), frontiers in Molecular Neuroscience, Vol. 10, no. 182 (June. 14, 2017), pp. 1-20),
Keledjian teaches a method of treating and ameliorating Gulf War illness or syndrome in a subject (rats), the method comprising: orally administering to the subject in need thereof a therapeutically effective amount of rosiglitazone, a PPAR-gamma agonist (See e.g. Pages 3-7; Materials and Methods). Keledjian further teaches that rats showed improvement in novel object recognition assessing memory function (See Page 5; Novel Object Recognition).
(Of note, the applicant defines a subject in the specification as a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Therefore, all references incorporate the Applicant’s subject. Keledjian’s aforementioned methods of treating and ameliorating Gulf-War illness or syndrome encompass the Applicant’s claimed method of effecting neuroprotection in a subject in need thereof, since Keledjian’s methods are achieved through effecting neuroprotection of the subjects of the methods, thus claims 1,14, and 15 are obvious variants.)
However, Keledjian does not teach the administration of a nuclear factor erythroid 2-related factor 2 (Nrf2) agonist.
Zhang teaches administration of t-BHQ to rats intraperitoneally, and that t-BHQ, an Nrf2 agonist, ameliorates neurobehavioral deficits, promotes Nrf2 nuclear activation and attenuates oxidative damage, suppresses neuroinflammation in cerebral cortex, and inhibits neuronal apoptosis and reduces neuronal cell death in Hypoxic-ischemic encephalopathy, through addressing oxidative damage in the brain (See e.g. page 17; Highlights).
Shetty further teaches that Nrf2 is a transcription factor that is well recognized for its role in regulating antioxidant proteins that guard against oxidative damage elicited by injury or inflammation (See Introduction; page 2, paragraph 3), and that conditions replicating Gulf-War Illness in rats were associated with considerable activation of Nrf2 in the hippocampus (See Results; page 11, paragraph 1).
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
While Keledjian, Zhang and Shetty do not teach the Applicant’s dosing of t-BHQ to be 1.0 mg to 5.0 mg/kg body weight per day, one skilled the art, before the effective filling date of the claimed invention, would have had motivation to optimize the dosing t-BHQ through routine experimentation once Nrf2 agonism was established as a result-effective variable. "[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Additionally, routine routes of administration such as oral, subcutaneous, and intraperitoneal are obvious to try and one in the art would have had teaching, suggestion, or motivation, before the Applicant’s effective filing date. to use these routes of administration in the Applicant’s method.
While Keledjian, Zhang, and Shetty do not explicitly teach pioglitazone as a PPAR-gamma agonist through working example, Keledjian mentions that thiazolidinediones such as rosiglitazone and pioglitazone are potent agonists of PPARγ that induce significant neuroprotection in animal models of CNS disease (See e.g. page 3; paragraph 2). Pioglitazone is an obvious species within the thiazolidinedione drug class, and Keledjian teaches another well-known thiazolidinedione, rosiglitazone, which is known in the art to have the same mechanism of action and comparable pharmacokinetic parameters as pioglitazone, such that one skilled in the art, before the effective filling date of the claimed invention, would have had sufficient teaching, suggestion, or motivation to try both rosiglitazone and pioglitazone, with various routine routes of administration such as oral, subcutaneous, and intraperitoneal dosing in methods to treat Gulf-War illness or syndrome in a subject. Of note, the Applicant also discloses rosiglitazone as an alternative and supports rosiglitazone as an obvious variant (See e.g. page 8; paragraph 25).
While Keledjian, Zhang, and Shetty do not teach the Applicant’s dosing of pioglitazone to be 0.1 mg to 0.4 mg/kg body weight per day, one skilled in the art, before the effective filing date of the claimed invention, would have had motivation to optimize the dosing of both pioglitazone and rosiglitazone through routine experimentation once PPAR-gamma agonism was established as a result-effective variable, and since pioglitazone and rosiglitazone are closely related species of compounds that have comparable properties and are routinely substituted. "[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over
Keledjian, K. (The peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone, ameliorates neurofunctional and neuroinflammatory abnormalities in a ratmodel of Gulf War Illness), PLOS ONE, Vol. 15, no. 11 (Nov. 13, 2020), pp. 1-21), in view of
Zhang, J. (Tert-butylhydroquinone Post-treatment Attenuates Neonatal Hypoxic-ischemic Brain Damage in Rats), Neurochem Int., Vol. 116, (June, 2018), pp. 1-12), further in view of
Shetty, G.A. (Chronic Oxidative Stress, Mitochondrial Dysfunction, Nrf2 Activation and Inflammation in the Hippocampus Accompany Heightened Systemic Inflammation and Oxidative Stress in an Animal Model of Gulf War Illness), frontiers in Molecular Neuroscience, Vol. 10, no. 182 (June. 14, 2017), pp. 1-20), further in view of
Bennett, B.L. (SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase), PNAS, Vol. 98, no. 24 (November. 20, 2021), pp. 13681-13686, further in view of
Wang, D. (Vaccination alone or in combination with pyridostigmine promotes
and prolongs activation of stress-activated kinases induced by
stress in the mouse brain), Journal of Neurochemistry, Vol. 93, (2005), pp. 1010-1020.
(Of Note: Claim 10 has been previously rejected under 35 U.S.C. 112a for failing the written description requirement, as Applicant fails to sufficiently describe “transcription factor modulators”, other than the species SP600125 as an example. The following 35 U.S.C. 103 rejection applies to the extent the transcription factor modulator as claimed, is SP600125.)
Keledjian teaches a method of treating and ameliorating Gulf War illness or syndrome in a subject (rats), the method comprising: orally administering to the subject in need thereof a therapeutically effective amount of rosiglitazone, a PPAR-gamma agonist (See e.g. Pages 3-7; Materials and Methods). Keledjian further teaches that rats showed improvement in novel object recognition assessing memory function (See Page 5; Novel Object Recognition).
However, Keledjian does not teach the administration of a nuclear factor erythroid 2-related factor 2 (Nrf2) agonist, or its relevance to Gulf-War Illness.
Zhang teaches administration of t-BHQ to rats intraperitoneally, and that t-BHQ, an Nrf2 agonist, ameliorates neurobehavioral deficits, promotes Nrf2 nuclear activation and attenuates oxidative damage, suppresses neuroinflammation in cerebral cortex, and inhibits neuronal apoptosis and reduces neuronal cell death in Hypoxic-ischemic encephalopathy, through addressing oxidative damage in the brain (See e.g. page 17; Highlights).
Shetty teaches that Nrf2 is a transcription factor that is well recognized for its role in regulating antioxidant proteins that guard against oxidative damage elicited by injury or inflammation (See Introduction; page 2, paragraph 3), and that conditions replicating Gulf-War Illness in rats were associated with considerable activation of Nrf2 in the hippocampus (See Results; page 11, paragraph 1).
Wang teaches that inhibiting JNK may be useful for treatment of Gulf-War Illness (See page 1019; paragraph 2). Wang also teaches that the activation of stress kinases such as JNK are relevant for Gulf-War Illness and have been implicated in many neurological disorders such as Alzheimer’s, Huntington’s, and Parkinson’s diseases and amyotrophic lateral sclerosis (See page 1018; paragraph 3).
However, Wang does not teach a species of compound to inhibit JNK to affect Gulf-War Illness.
Bennett teaches a species of transcription factor modulator, SP600125, and that it is an inhibitor of JNK (See Page 1; Abstract).
It would have been obvious to one skilled in the art, before the Applicant’s effective filling date, to combine the Keledjian’s teaching of using PPAR gamma agonist in a method of treating Gulf-War illness in a subject, and Zhang and Shetty’s teaching of using an Nrf2 agonist in a method of treating Gulf-War illness in a subject, with Wang’s teaching of JNK inhibition as a mechanism for treating Gulf-War illness, and Bennett’s teaching of a transcription factor modulator, SP600125, that is able to inhibit JNK, to arrive at the Applicant’s claimed method of treating Gulf War illness or syndrome in a subject, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-y) agonist and a nuclear factor erythroid 2-related factor 2 (Nrf2) agonist, further comprising administering a therapeutically effective amount of one or more transcription factor modulators.
One having skilled in the art would have sufficient teaching, suggestion, and motivation prior to the Applicant’s effective filling date, to combine the PPAR-gamma agonists pioglitazone and rosiglitazone, and the Nrf2 agonists t-BHQ and sulforaphane, with the relevant transcription factor modulator SP600125, in a composition that has routinely optimized doses of all components, that is then used in a method to treat, affect, or any obvious variations thereof, Gulf-War illness in a subject wherein the method treats one or more standard symptoms of Gulf-War Illness.
Conclusion
No claims are allowed.
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/OROD MOTEVALLI/Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628